German Center for Infection Research ANNUAL REPORT
2013
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DZIF at a glance The German Center for Infection Research (DZIF) coordinates and oversees the strategic planning of translational infection research within Germany. Its mission is to translate the results from basic biomedical research into clinical research. 32 DZIF research centres are working concertedly against the global threat presented by infectious diseases.
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Table of contents
Editorial
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About DZIF
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Science – Translation in focus Emerging Infections
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Tuberculosis
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Malaria
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HIV
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Hepatitis
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Gastrointestinal Infections
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Infections of the immunocompromised Host
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Healthcare-associated and Antibiotic-resistant bacterial Infections
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Novel Antiinfectives
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Research infrastructures Product Development Unit
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Clinical Trial Unit
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African Partner Sites
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Natural Compound Library
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Biobanking
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Bioinformatics
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DZIF Academy
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Collaborations in DZIF
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DZIF Highlights 2013
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Science and public
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External collaborations
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German Health Research Centres
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Facts and figures Organisations and bodies
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Partner sites and member establishments
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Finance
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Personnel und awards
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Publications
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Editorial
Yet we may have rested on our laurels for too long and antiinfectives could become victims of their own success. An increasing number of pathogens are becoming resistant to the available medicines. The loss of control over infectious diseases is unsettling researchers, clinicians and the entire healthcare system alike. These and other global challenges relating to infection are at the core of DZIF’s endeavours. In addition to developing new approaches for the diagnosis and therapy of the most important healthcare-related infectious diseases worldwide, DZIF is paying special attention to emerging pathogens, nosocomial infections in the immunocompromised host and the development of novel candidate antimicrobial agents. Specialised competence centres within DZIF are dedicated to these topics, where clinical infectiologists and basic researchers from different establishments collaborate closely. This networking of universities, university medical centres and non-university research establishments into competence centres combines expertise, creates synergies and allows rapid translation into clinical practice. The results selected for this Annual Report illustrate the paths we have taken, from releasing a new malaria vaccine, to ‘antibiotic stewardship’ for containing bacterial resistance, to our dedication to educating qualified physicians and scientists in infection research. All these activities of the past three years demonstrate the new translational potential of the institutes cooperating within DZIF.
DZIF e.V. Executive Board
Prof Dr Martin Krönke
Prof Dr Ulrike Protzer
Prof Dr Dirk Heinz
Editorial
In the middle of last century, antibiotics revolutionised medicine and all but eliminated the threat posed by many bacterial infectious diseases. Improved hygiene and prophylactic vaccines against infections have saved more human lives than all other medical interventions. Without these accomplishments, today’s advanced and intensive medicine would be inconceivable.
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About DZIF
About DZIF
DZIF: New integrative and interdisciplinary research approaches
In spite of antibiotics and vaccinations, infections are still a major threat to human health worldwide. Alongside chronic and poverty-associated infectious diseases, we also face newly emerging microbial and viral infections. Posing another serious threat are the resistances pathogens are developing against the conventional antibiotics in use. And there is another problem. In industrial countries, especially, advanced medicine is actually clearing a path for infections in medically immunosuppressed patients, especially in the fields of transplant medicine and oncology. In light of all this, the German Center for Infection Research (Deutsches Zentrum für Infektionsforschung, DZIF) is taking an integrative approach. It brings experts
in translational research, epidemiology and clinical practice together to share their insights. Cooperating within DZIF, with funding from the German Federal Government and Länder, are universities, university medical centres, Leibnitz and Max Planck Institutes, Helmholtz Centres and Federal research establishments with strong profiles in the field of infectious diseases. Competence centres with international visibility DZIF’s mission is to coordinate and strategically align translational infection research in Germany – i.e. research at the preclinical–clinical interface. DZIF is thereby making a substantial contribution towards the effective and efficient development of new diagnostic, preventive and therapeutic methods for treating infectious diseases.
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… DZIF overcomes institutional boundaries DZIF also serves as a link between basic research and the biotech and pharmaceutical industry. Good manufacturing practice (GMP), good laboratory practice (GLP), validated animal models and professionally-designed clinical trials are core components of the DZIF concept. The centre is a common contact for national authorities such as the Robert Koch, Friedrich Löffler and Paul Ehrlich Institutes, as well as the Federal Institute for Drugs and Medical Devices, with which research activities are coordinated or jointly conducted. Preclinical and clinical research DZIF puts German infection research in a position to continue targeted development of fundamental findings in a preclinical and clinical direction. Advancements in translational research will allow DZIF and other institutions in the public and private health sectors to develop new diagnostic methods, anti-infectives and vaccines. The effectiveness of DZIF’s operations can be seen from the example of the newly emerged “Middle East respiratory syndrome coronavirus” (MERS-CoV). DZIF was instrumental in developing a diagnostic assay and a vaccine for MERSCoV. Representatives from various TTUs are available as advisors in Saudi Arabia. Together, the DZIF scientists are helping to curb MERS and other infectious diseases and provide timely help to patients.
DZIF groups its research activities into nine Thematic Translational Units (TTU) and six interdisciplinary Translational Infrastructures (TI):
Thematic Translational Units (TTU) • • • • • • • •
Emerging Infections Tuberculosis Malaria HIV Hepatitis Gastrointestinal Infections Infections of the immunocompromised Host Healthcare-associated and Antibiotic-resistant bacterial Infections • Novel Antiinfectives
Translational Infrastructures (TI) • • • • • •
Product Development Unit Clinical Trial Units African Partner Sites Natural Compound Library Biobanking Bioinformatics
• DZIF Academy
About DZIF
Infections know no national boundaries … Cross-border collaboration is of pivotal importance at DZIF. Given that most infections occur worldwide and the health systems of developing and newly-industrialised countries are facing major problems, DZIF systematically involves partners from international organizations and from countries on the African continent, in particular, in its work.
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Emerging Infections
Science – Translation in focus
Broad-spectrum war on viruses
Safety clothing is mandatory when handling little-researched pathogens.
Epidemics of new infectious diseases require rapid intervention to prevent them from spreading any further. In the TTU “Emerging Infections” of DZIF, scientists from universities, university clinics and the public health service are collaborating closely to research and combat such diseases. In the summer of 2012, a 60-year-old man died in Jeddah, Saudi Arabia, after nearly three weeks of suffering from lung and kidney failure. It all started with harmless cold-like symptoms. Found lurking in the patient’s bronchial secretions was the previously unknown Middle East respiratory syndrome coronavirus (MERS-CoV). By the end of 2013, 176 people had already fallen ill with MERS. Researchers at DZIF’s Bonn-Cologne site quickly developed the standard test for high-certainty detection of MERS in 2012, working from genome sequences.
Then, in 2013, DZIF scientists led by Prof Gerd Sutter of Ludwig-Maximilians-Universität München started working on developing a vaccine. For this, they used tested, safe vaccination viruses. MERS vaccine within reach They genetically manipulated the viruses to produce the same envelope protein as MERS-CoV. In infected host cells, it becomes anchored in the cell membrane and stimulates MERS-CoV-specific immune responses after vaccination. The Erasmus Medical Center Rotterdam and Philipps-Universität Marburg were also involved in the research work. In mice, the test vaccine based on Modified Vaccinia virus Ankara (MVA) promotes the formation of antibodies that effectively block cell infection with MERS-CoV. Now the researchers need a suitable animal model that mimics the human disease more closely, since mice do not naturally fall ill from MERS. “Development of
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New mosquitoes and parasites in Germany In a large-scale monitoring programme led by Prof Egbert Tannich und Dr Jonas Schmidt-Chanasit, scientists at the Bernhard Nocht Institute for Tropical Medicine in Hamburg recorded the populations of mosquitoes in Germany and the pathogens they carry. With the support of various cooperation partners, a total of 130,000 mosquitoes were studied in 2013. The researchers discovered that the Asian tiger mosquito (Aedes albopictus) is regularly carried from southern Europe into southern Germany with road traffic. This mosquito can carry tropical viral diseases such as dengue and chikungunya fever. In Brandenburg and Saxony-Anhalt, the researchers detected larvae of the canine skin worm Dirofilaria repens in three mosquito species. This parasite occurs in dogs, the weasel family and foxes in southern and eastern Europe, Africa and Asia. Infected mosquitoes can also infect humans. “A locally acquired Dirofilaria infection was recorded for the first time recently in a patient from Saxony-Anhalt. Exactly how at-risk of contraction people are in Germany will have to be investigated in further epidemiological studies,” Tannich reports. Other research focuses of the TTU are the immunological and epidemiological characteristics of emerging infectious diseases and their clinical treatment. Rapid and reliable methods for detecting new pathogens must be developed and guidelines established on how to proceed with infected patients. The TTU also intends to develop new broad-spectrum antiviral medicines and active agents against diseases such as dengue fever and West Nile fever. Coordinator: Prof Dr Stephan Becker, Marburg
• New viral diseases are emerging continually and in most cases unexpectedly. One current example is the Middle East respiratory syndrome coronavirus (MERS-CoV). • They require rapid intervention to prevent them from spreading. • Pathogens and new mosquito species are introduced into Europe by travel and freight transport. • Mosquitos are transmitting exotic diseases more frequently throughout Europe. These include dengue, West Nile and chikungunya fever and Malaria tertiana.
Science – Translation in focus
an approved vaccine against MERS-CoV will likely take several more years, since it has to go through several clinical trial phases before approval,” Sutter explains.
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Tuberculosis
Science – Translation in focus
Resistant pathogens in the spotlight
A tuberculosis patient is in good hands at the Medical Clinic Borstel.
German tuberculosis researchers are among the best in the world. To ensure their results are applied more rapidly for the benefit of patients, the TTU “Tuberculosis” of DZIF was created. Results from basic research flow directly into the prevention, diagnosis and therapy of tuberculosis. The TTU includes DZIF Munich, Tübingen, Hannover-Braunschweig and Hamburg-Lübeck-Borstel. The researchers are concentrating above all on combatting multidrug-resistant and extensively drug-resistant pathogens of M/XDR tuberculosis, which are resistant to conventional antibiotics. Important aims are effective protection against M/XDR tuberculosis and better treatment for patients. Treatment of M/XDR tuberculosis has so far been of limited success. The drugs used are expensive and often have severe side-effects. While the World Health Organization recommends combination therapy over 20 months for all patients, many patients stop their therapy before the
end of the full term. As a consequence, the disease breaks out anew. How long treatment has to continue in each case is unpredictable and can vary substantially between individuals. As part of the TTU‘s work, scientists at the Research Center Borstel are looking for ways to adapt the treatment optimally to each patient and reduce the stress of side-effects. To this end, they are identifying biomarkers that reveal how the body responds to the therapy. Alongside immunological parameters, chemists are studying lipids as a novel biomarker in patient samples. To verify their suitability, the researchers have recruited a cohort of M/XDR tuberculosis patients throughout all of Germany, whose progress on therapy will be monitored and analysed. Basic research and clinical practice closely linked At the medical clinic of the Research Center Borstel, an area has been set aside for the inpatient and outpatient care of tuberculosis patients. The results from basic
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• Tuberculosis is caused by bacteria of the Mycobacterium tuberculosis complex.
• Worldwide around 8 million new cases are recorded each year, with 1.4 million fatalities. Trend: gradually declining. • The increase of multidrug-resistant strains that are especially difficult to treat is a major problem. Trend: dramatically increasing, especially in eastern Europe.
research flow directly into the treatment of the patients there. Physicians can call the TBinfo Service of the TTU “Tuberculosis” at any time for advice. Advanced clinical education courses, a national M/XDR-TB Consilium and specific guidelines all ensure the scientific results find their way into practice. Tracking down antibiotic resistance In order to better monitor the spread of M/XDR-TB and detect the emergence of new resistance to antibiotics in future, a laboratory unit for high-throughput analyses of bacterial genomes has been established in Borstel. Using ultra-modern sequencing technology, the researchers have access to the entire bacterial genome, including the resistance genes. This allows them to follow the propagation of the bacteria and identify chains of infection. One breakthrough was achieved with the identification of “outbreak strains” that are transmitted extremely often and are already resistant to most antibiotics in eastern Europe. An aim of the researchers is to characterise the genetic background of the outbreak variants and discover the causes of their successful propagation. A further aim is to map tuberculosis outbreaks in Africa and study tuberculosis strains of the African DZIF partner institutes – focussing on the emergence and propagation of antibiotic resistance.
To coordinate research projects with partners in Africa, and in future in eastern Europe as well, an “International Clinical Trials Center” has been established at the hospital of Ludwig-Maximilians-Universität München. External partners were gained early on to support the study of the emergence of antibiotic resistance and its characterisation at the high-throughput analytical laboratory in Borstel. Furthermore, the researchers of the TTU “Tuberculosis” are testing natural substances with the aim of developing novel tuberculosis medicines. They have created a preclinical testing station for anti-tuberculosis substances that simulates the conditions in the human body. The clinical testing of these substances is a joint effort with the major European-African trial networks. Coordinator: Prof Dr Stefan Niemann, Borstel
Science – Translation in focus
• One in every three people in the world might be infected with M. tuberculosis during a lifetime.
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Malaria
Science – Translation in focus
Malaria: Old challenge, new ideas
The search for a suitable vaccine against malaria continues.
Even today, it is difficult to combat malaria effectively. Efforts often fail due to regional differences between pathogens and their rapid adaptation. Co-infections further complicate its treatment. Yet the biggest problem physicians are facing is the increasing resistance to anti-malarial drugs. The TTU “Malaria” of DZIF has been established to develop potential vaccines further in order to allow effective immunisation of people in malaria-endemic areas. They will also be identifying and clinically testing novel agents against malaria. To plan the proper therapies, researchers are also investigating in epidemiological studies when and where malaria pathogens appear and how they spread. Three DZIF establishments are jointly investigating this tropical disease: the Heidelberg University Hospital, the
Institute for tropical medicine of the University Hospital Tübingen and the Bernhard Nocht Institute in Hamburg. The TTU is further reinforced by intensive cooperation with three African partner institutes in Burkina Faso, Gabon and Ghana. This gives the DZIF researchers access to samples and data from regions in which malaria is widespread. Clinical trials on new medicines and vaccines can also be carried out directly in endemic areas. New vaccination method in clinical trial One example of the TTU’s work is a clinical phase I trial initiated in 2013 at the Institute of Tropical Medicine of the University Hospital in Tübingen. The research team of Dr Benjamin Mordmüller is testing the effectiveness and safety of a new approach to malaria vaccination. The researchers inject volunteers with viable parasites while
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In the spring of 2013, the Tübingen group had already been involved in the preparation of another clinical trial at the partner site, the Albert Schweitzer Hospital in Lambaréné, Gabon. Using the human malaria infection model established within DZIF, the importance of the sickle-cell gene and acquired immunity is being investigated. Mathematics for better predictive models In order to widen the possibilities for statistical evaluation and modelling of research data, the research group “Mathematical Modelling and Biostatistics” was established at the Bernhard Nocht Institute. Here, scientists are creating mathematical models to describe the appearance and lifecycle of parasites in the blood of infected people as well as the development of the pathogens in the human body. These models will also allow them to analyse seasonal and geographical fluctuations in the spread of the parasites and thereby better estimate the frequency of illness.
• Malaria occurs mainly in tropical regions. • It is widespread in most of sub-Saharan Africa where the incidence rate and mortality is especially high in children. • According to the WHO, in 2012 approximately 627,000 people died from malaria and 207 million were infected worldwide. • The malaria pathogens (plasmodium parasites) are transmitted to people by mosquitoes.
In Heidelberg, further projects of this TTU are focussing on how the immune system of infected volunteers responds to infection, and on the development of novel drugs against malaria. With the help of molecular diagnostic techniques, the TTU is also investigating how often African children suffer from malaria co-infections, how greatly they are at risk and how these infections can be treated. Coordinator: Prof Dr Peter Kremsner, Tübingen
Science – Translation in focus
simultaneously administering an anti-malarial that weakens the plasmodia. The desired result is lasting immunisation. “Because conventional preventative approaches are so far disappointing, we are testing new, at first sight astonishing methods,” Mordmüller says.
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HIV
Science – Translation in focus
New approaches to controlling and healing HIV infection
Both a physician and a researcher: Dr Jörg Janne Vehreschild at the intensive care unit of the University Hospital Cologne.
Around 30 years after the discovery of HIV as the cause of the immunodeficiency disease AIDS, present-day researchers must focus on the prevention of new HIV infections, the medical treatment of HIV patients, and the healing of HIV infections. These are the focuses of the TTU “HIV” of DZIF. Cutting HIV out of the host genome HIV is a retrovirus. When it infects a cell it must make sure the newly infected cell transcribes the virus’s genetic material, consisting of RNA, into DNA and then integrates it stably into the host cell’s own chromosomal DNA. Successful integration is crucial for infection; the integrated viral RNA can then lead to the production of new viruses or remain latent over a very long time. As yet little is known about the laws governing HIV’s integration into human DNA. The TTU “HIV” is studying this
issue intensively. The DZIF researchers want to understand how and where the host cell integrates the foreign DNA, how the foreign sequences are read and how, under certain circumstances, it is muted and therefore remains latent over several years before suddenly being reactivated to new virus production. This will lead to ways in which to eliminate latent viruses. The viral DNA in the host cell’s chromosome is the target of a new strategy for eliminating latent infections. The researchers are attempting to cut out the viral genome using a modified form of the enzyme Tre recombinase, which specifically recognises HIV sequences. In this project, involving the Heinrich Pette Institute, the University Medical Center Hamburg-Eppendorf and Heidelberg University, the scientists have developed a genetic engineering technique by which to produce this Tre recombinase in stem cells. “We are currently verifying
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• Worldwide 34 million people are infected with HIV, 70 percent of them in sub-Saharan Africa.
• The number of AIDS fatalities is dropping each year, but the incidence of new infections is as high as ever. • Vaccination and complete healing are so far impossible. • HIV is extremely genetically variable and can remain latent inside infected cells for a very long time. • Primary goals: prevent, treat and ideally heal HIV infection.
the effectiveness with which Tre recombinase cuts the viral DNA out of the host genome,” says Prof Hans-Georg Kräusslich, coordinator of the “HIV” TTU. Systematically documenting patient data In the mid 1990s, after the discovery of HIV, drugs that suppress reproduction of the virus were developed. While these drugs help the patients, they often have strong side-effects. They can lead to organ damage in the long term, and the virus may become resistant to them. Reliable recommendations depend on documentation of the highest quality. Only by standardised observation over several years can important causal relationships be established. In many cases, the reasons for treatment failure or adverse events remain unclear. Additionally, basic researchers need information and biological samples if they are to identify the causes. The TTU “HIV” began setting up a scientific platform for these purposes in 2013. A junior group led by Dr Jörg Janne Vehreschild with a methodical and medical informatics focus was initiated at University Hospital Cologne. One of the first duties of this group was requirements pl-
anning with the partners of the “HIV” TTU. In collaboration with the Robert Koch Institute, a common IT solution is now being implemented at all locations. This makes it possible to document patient data systematically. These data can then be transmitted between centers and international partners in standardised form. Furthermore, biomaterial – such as tissue samples or biopsies – can be recorded with the storage location and a link to the clinical record. “For our collaboration in the TTU to be a success, it is decisive for us to gain and exchange harmonised data and sample material,” Vehreschild says. “For this, we have successfully developed a common ethics and data safety concept for all locations.” Coordinator: Prof Dr Hans-Georg Kräusslich, Heidelberg
Science – Translation in focus
• Effective antiretroviral therapies are increasingly available.
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Hepatitis
Science – Translation in focus
Focusing on improving therapy
Optimism in the fight against hepatitis B: Prof Ulrike Protzer and Dr Jan-Hendrik Bockmann.
Researchers of the TTU “Hepatitis” want to improve the prophylaxis against chronic viral hepatitis and develop therapies to cure it. They intend to explain the role of resistance to antiviral drugs, and to identify novel targets for the development of improved drugs. The available antiviral drugs cannot cure hepatitis B. If treatment is interrupted, then hepatitis B reactivates. The template for hepatitis B virus replication is the so-called “cccDNA”. This is a stable circular DNA form which the virus deposits in the nucleus of infected liver cells to persist. Molecular mechanism to eliminate cccDNA discovered Under the umbrella of DZIF, scientists working with Prof Ulrike Protzer and Prof Mathias Heikenwälder of Technische Universität München and Helmholtz Zentrum München, together with national and international partners, have discovered how the viral cccDNA can be eliminated. The researchers showed that, after administering inter-
feron-α, expression of the enzyme APOBEC3A is induced in the infected liver cells. This enzyme cuts amine groups out of the cytosine bases of the nuclear cccDNA, thereby initiating its degradation. The same effect can be achieved by activating the lymphotoxin-ß receptors to stimulate expression of the deaminase APOBEC3B. The genome of the liver cells remains unaffected. “The activation of deaminases is an interesting starting point for developing new therapies that allow us to cure hepatitis B,” explains Ulrike Protzer. Mode-of-action of cyclophilin antagonists identified To reproduce its RNA genome, the hepatitis C virus is dependent on proteins from liver cells. For example, binding of the cellular protein cyclophilin A to the viral protein NS5A promotes replication of the viral genome. Cyclosporine derivatives that inhibit cyclophilin are potential candidates for new antiviral drugs. These are currently being tested in clinical trials.
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Other focuses The active agent Myrcludex-B developed by DZIF researcher Prof Stephan Urban is currently in clinical trials. It binds to the cellular receptor for hepatitis B viruses and thus blocks the spread of viruses in the liver. In the mouse model, it helps control the virus. Initial trials in patients are being initiated with the help of DZIF. With broad-based epidemiological studies, the TTU “Hepatitis” intends to define the therapeutic need in Germany and to make treatment options accessible to patients. In addition, the TTU is searching for biomarkers that will allow prediction of the course of the disease, successful treatment and finally the chance of a cure. It is furthermore striving to improve the infrastructure for creating patient cohorts and for supporting clinical trials. Coordinator: Prof Dr Michael Manns, Hannover
• Viral hepatitis (liver inflammation) is caused by the hepatitis viruses A to E. • Hepatitis A and E viruses are transmitted mainly through water and food contaminated with infectious faeces; hepatitis B, C and D viruses are typically transmitted by direct blood contact or – mainly in the case of hepatitis B virus – through sexual contact. • Around half a billion people in the world, one million in Germany, are chronically infected with hepatitis B, C and D viruses. They are at high risk of developing liver cirrhosis or hepatocellular carcinoma; more than one million humans die from this each year. • Vaccines exist for hepatitis A and hepatitis B, but not for hepatitis C or hepatitis E.
Science – Translation in focus
A research group working with DZIF scientist Prof Ralf Bartenschlager of the Heidelberg University Hospital has shown that cyclophilin-A inhibitors effectively block reproduction of the hepatitis C virus genome by inhibiting the formation of new virus-induced membrane vesicles in infected cells. These membrane vesicles provide the essential scaffold for the coordinated sequence of viral reproduction steps, and serve to protect the viral RNA against RNA-degrading cellular enzymes. The antiviral action of cyclophilin antagonists is directly dependent on the viral protein NS5A. If cyclophilin is sequestered by the inhibitors, then NS5A is unlikely to fold correctly and, consequently, no membrane vesicles will form. “With that, we have discovered a new principle of antiviral therapy. Also, compared to direct NS5A inhibitors, therapy resistance to cyclophilin inhibitors is much less likely to develop,” Bartenschlager says.
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Gastrointestinal Infections
Science – Translation in focus
New drugs against gastrointestinal microbes
Patient samples arrive at the microbiological laboratories of Hannover Medical School.
With the TTU “Gastrointestinal Infections”, DZIF intends to improve the diagnosis, treatment and prevention of gastrointestinal infections. The scientists in Braunschweig, Hannover, Munich, Tübingen, Cologne and Münster are interested in bacterial pathogens such as EHEC, Helicobacter pylori and salmonellae. The researchers are aiming at novel therapy strategies targeted against a specific bacterium or group of germs. This will ensure only pathogens are attacked and not the natural organisms in the digestive tract, as is the case with existing therapies. The bacterium Helicobacter pylori is a dangerous microorganism. Every second person carries it. Many people contract stomach ulcers or even stomach cancer from this infection. The possibilities for treatment are limited and there are no vaccines against the bacterium so far.
A project of Technische Universität München in collaboration with Hannover Medical School has made significant progress. The group led by Munich microbiologist Prof Markus Gerhard is preparing a clinical phase I trial for a vaccine against H. pylori. If it succeeds and is approved it will be the first vaccine against this bacterium. The advantage of this is that, until now, most patients who have fallen ill from H. pylori have been treated with antibiotics. Such treatment is difficult and is also losing its potency because strains of the pathogen are becoming resistant. Helicobacter vaccine within reach The new vaccine contains essential components of the bacterium complemented with an adjuvant – a substance that boosts the immune system’s defensive response. Now that the vaccine has been tested in mice and monkeys, the scientists intend to test its effectiveness and
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Analysis of the gut flora pays off Another focus of the TTU is therefore to research new therapeutic approaches against pathogenic gut microbes in consideration of the natural gut flora. Digestion in the stomach and intestine only works thanks to the countless beneficial bacteria that live there. Scientists call the entirety of GI microbes the microbiota; it is of enormous importance to our health. The TTU researchers are looking to use specific molecular and genetic traits of the microbiota as biomarkers to improve our understanding of bacterial gastrointestinal infections, and to develop individual treatments against them. As of autumn 2013, they have been building a cohort of patients whose gut flora has been analysed multiple times during their time in hospital. This will allow the researchers to detect biomarkers that indicate, for example, an elevated risk of infection with Clostridium difficile – the bacterium considered the most significant cause of diarrhoea infections in hospitals. The preparations for recruiting suitable patients and for testing and evaluating samples have been concluded. At the end of 2013, the cohort comprised around 200 patients and the study will eventually include up to 2000 patients in total. In other projects of this TTU, a Germany-wide active centre is being established for fundamental research into the microbiome. Medical professionals at the University of Tübingen and Ludwig-Maximilians-Universität München are developing new animal models, for instance, by which innovative treatment strategies can be tested very reliably at a preclinical stage. Coordinator: Prof Dr Sebastian Suerbaum, Hannover
Science – Translation in focus
safety in people. In preparation for the clinical trial, they have set up test systems for the vaccine and analysed the diversity of the antigens present in the vaccine. The results look good for the success of the clinical trial – and with it for an important step forward in the fight against this dangerous gastric germ.
• E very year, more than three million people worldwide die from infectious gastrointestinal diseases. • At greatest risk are children and people with a weakened immune system. • Helicobacter pylori is found in 50 percent of the world’s population and can cause stomach ulcers and stomach cancer.
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Infections of the immunocompromised Host
Science – Translation in focus
Protecting transplant patients against infections
Researchers at TU München search for immune cells with a “good memory”.
It is a serious problem in hospitals. For immunocompromised patients, pathogens that are normally harmless can suddenly become a life-threatening danger. The reasons for this increased susceptibility and the various possibilities for protecting these patients are being studied within DZIF at several locations. The TTU “Infections of the immunocompromised Host” is a platform on which the expertise of the individual groups is being bundled and their activities intensified. DZIF researchers are investigating at several locations – Munich, Hannover-Braunschweig, Heidelberg and Tübingen – what molecular, cellular and/or genetic causes underlie the increased susceptibility to infections of immunocompromised patients. They aim to identify biomarkers by which they can better estimate the individual risk
of infection, and to develop novel drugs and treatment methods in order to transfer this knowledge from bench to bedside. DZIF transplant cohort formed In 2013, the DZIF scientists initiated a core project of the TTU: a one-of-a-kind transplant cohort in Germany. The DZIF Transplant Cohort includes patients who have received a donor organ or who have received haematopoietic stem cell transplantation (HSCT). The researchers will be collecting and analysing medical data and biological samples from these patients over a long period. Background: After a transplantation, patients often depend for the rest of their lives on medication in order to prevent rejection responses. However, these drugs make
T-cells against infection Scientists led by Prof Dirk Busch of Technische Universität München are investigating how to reduce the risk of infection in patients after HSCT. “We are concentrating on infections with pathogens that can reside permanently in healthy people,” says Busch. “In the case of immunodeficiency, these pathogens can be reactivated and cause severe symptoms.” Some examples are herpes viruses such as cytomegalovirus and Epstein-Barr virus. The scientists’ intention is to treat patients by giving them specific immune cells that actively attack these pathogens. The method is called adoptive cell therapy.
• People with a weakened immune system are at especially high risk of infection with viruses, bacteria, fungi or parasites. • At particulary high risk are transplant patients, the chronically ill, people with hereditary or acquired immunodeficiencies and the elderly. • They require special medication because conventional antiinfectives often do not help.
the patients more susceptible to infection. The problem is far from new, but there are many questions still unanswered. For instance, what differences exist between individual patients regarding susceptibility, and how do certain infections affect the long-term success of the transplant and the patient’s survival. So far, the organisational basis has established for effective collaboration between the transplant clinics and scientific institutes involved. Furthermore, an Ethical and Privacy Policy and a protocol for collecting samples in biobanks have been established.
The cells administered are called T-lymphocytes, or T-cells for short. They search the body for pathogens and, after specific detection, can eliminate infected cells. In various subprojects, the researchers are working on characterising different sorts of T-cells and their activity in greater detail. An important result in 2013 was the discovery that so-called central memory T-cells (TCM) are especially suitable for adoptive cell therapy, requiring administration of just a few cells. Now the researchers intend to develop methods for treating patients with these cells. After promising preclinical work, the new method of TCM transfer will soon be tested clinically for infection prophylaxis in patients after HSCT. As soon as all regulatory requirements have been approved (probably by the end of 2014), the first patients will receive purified donor-derived TCMs as part of a DZIF-funded clincal trial. These cells are expected to protect against a variety of different pathogens. The researchers obtain them from healthy stem cell donors by a newly developed method. The main goal of the trial is to demonstrate the clinical safety of the novel approach, as well as to obtain first insights into clinical efficacy. Coordinator: Prof Dr Dirk Busch, Munich
Science – Translation in focus
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Healthcare-associated and Antibiotic-resistant bacterial Infections
Science – Translation in focus
New agents and therapies should curb healthcare-associated infections
Controlled use: Is using less antibiotics the key to reducing resistance?
Better hygiene, more targeted use of antibiotics and novel active agents are important in the fight against healthcare-associated infections. Despite these measures, the number of patients affected remains as high as ever. The biggest problems are presented by methicillin-resistant Staphylococcus aureus (MRSA) strains and by enterobacteria that produce extended-spectrum beta-lactamase (ESBL) enzymes that render the group of beta-lactam antibiotics ineffective. So far, too little is known about the causes and possible countermeasures. Also, there is a lack of clinical trials for testing new active agents. The TTU “Healthcare-associated and Antibiotic-resistant bacterial Infections” closes these gaps. The development of resistance of microorganisms is inextricably linked to the use of antibiotics. In a multicentre
trial, a group led by Prof Harald Seifert of the University of Cologne is investigating to what extent the introduction of an antibiotic stewardship programme would lower the consumption of antibiotics and, with it, the frequency of healthcare-associated infections caused by antibioticresistant bacteria. “Especially in times when the development of new antibiotics is floundering, careful use of antibiotics is of critical importance both in the field of ambulant medicine and in hospitals,” Seifert explains. Handling insidious enterobacteria Patients undergoing chemotherapy are at especially high risk of infection. ESBL-producing enterobacteria in the gut can cause severe septicaemia in these patients. In two trials led by PD Dr Maria Vehreschild of DZIF Bonn-Cologne, DZIF researchers are studying how to curb these often highly stubborn infections. One possible approach
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• The pathogens most frequently cause wound infections, urinary tract infections, pneumonia or septicaemia. • Treatment is becoming more difficult as many of the bacteria and fungi become multiresistant, in other words immune, to common antibiotics. • While these pathogens are only rarely a problem for healthy people, they can present a considerable danger for seriously ill, immunocompromised patients.
is to take isolation measures: “So far, it is unclear to what extent isolation, which is highly costly and stressful for the patient, prevents transmission between patients,” explains Prof Oliver Cornely. The researchers are also testing treatment with non-absorbable antibiotics to eliminate ESBL-producing enterobacteria from the gut.
“We are now producing new variants of these designer phage proteins and testing their action in comparison to mupirocin, the normal choice of antibiotic for treating staphylococci from the nasal mucosa,” Peschel explains. “By the end, we hope to have developed at least one phage lysin to sufficient maturity for testing in clinical trials.”
Designer phage proteins In a collaborative project of the University of Tübingen, the University of Münster and biotech firm Hyglos in Bernried, a group led by TTU coordinator Prof Andreas Peschel (Tübingen) is investigating the possibilities of using novel antibacterial agents derived from bacteriophages. Bacteriophages are viruses that specifically infect bacteria and then lyse them from the inside out using proteins.
As in Cologne, enterobacteria are the focus of another project at Gießen University. Researchers there are currently characterising the genome of these germs. In future, it should be possible to detect especially dangerous strains early on and prevent them from spreading. Furthermore, at the University Hospital Tübingen, Prof Evelina Tacconelli has been appointed professor of infectiology disease, creating a local platform for clinical trials.
The idea is to use the high specificity and bactericidal action of phages to eliminate S. aureus effectively without disrupting the human microflora. Certain phage lysin proteins shall be produced and used to attack resistant Staphylococcus aureus bacteria directly at their site of origin in the nasal mucosa. One phage protein studied in an initial set of trials acts highly specifically against S. aureus as hoped.
Coordinator: Prof Dr Andreas Peschel, Tübingen
Science – Translation in focus
• Nosocomial infections – those contracted in hospitals – are caused in most cases by bacteria or fungi, and in rare cases by viruses.
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Novel Antiinfectives
Science – Translation in focus
Activating silent reserves
Focus on defence: an activated immune system fights even concealed pathogens.
Drugs against bacterial or viral pathogens are hardly blockbusters – only a handful of antiinfective preparations generate a billion-dollar annual turnover. Their relatively meek economic presence is in contrast to their medical importance. Without novel antiinfectives, patients infected with resistant germs could find themselves without any options for therapy while advanced and intensive medicine would quickly reach their limits. The TTU “Novel Antiinfectives” of DZIF gives impetus to the development of these urgently-needed new drugs. Since life began, infectious pathogens have been an ever-present threat. A refined system of immunosensory receptors is capable of detecting the intrusion of pathogens early and, in most cases, manages to activate immunological defence mechanisms that can prevent the pathogens from spreading before an infection becomes manifest. “Toll-like receptors” (TLRs) and “retinoic acid
inducible gene I helicases” (RLHs) are of pivotal importance in this detection. They are located in the membranes or cytoplasm of immune cells and somatic cells, where they recognise characteristic nucleic acid structures of bacteria or viruses and can quickly activate our innate defence system. However, those pathogens that do cause manifest infectious diseases have done so by developing mechanisms to trick and subvert the host’s immunosensory detection system. DZIF scientists have now identified compounds based on synthetic, short-chain nucleic acids (oligonucleotides) that specifically bind to and activate TLRs and RLHs. These can be used to therapeutically activate the host’s highly effective innate defence mechanisms. Then even pathogenic organisms that can “hide” from the immune detection system can no longer propagate. Prof Gunther Hartmann of the University Hospital Bonn reports: “We were able to demonstrate in a series of animal models that these oligonucleotide
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Clinical use still a long way off Extensive preparations need to be made before the oligonucleotide ligands can be tested in humans. “We want to optimise the molecular architecture of the ligands so that they bind highly specifically and thereby direct the host’s innate immune defences even more effectively against bacteria and viruses,” Hartmann explains. “Our aim is to complement the classic antiinfectives, such as antibiotics, with the body’s natural defence mechanisms, in order to expand the antiinfective therapy spectrum and make life hard for the rising number of antibiotic-resistant germs.” Using silent genes for drug production Some parts of microorganism DNA are only transcribed into proteins under certain environmental conditions; at all other times these DNA regions remain “silent”. From analysing microbial genomes, it turns out that certain bacteria have many silent gene clusters that encode the synthesis of active compounds. Researchers in the TTU “Novel Antiinfectives” are activating such DNA regions and testing whether their products are useful for the treatment of infections. To this end, researchers working with Dr Tilmann Weber of the University of Tübingen have developed a new bioinformatics platform (antiSMASH) that can be used to track down such gene clusters (genome mining), and which also makes suggestions as to the planar structure of the corresponding compound. “After we used this to identify and activate silent gene clusters, we were actually able to isolate and characterise a promising class of compounds,” Weber reports. Other substances from the class of glycopeptides were already known but, after activating the silent gene clusters, they can be produced at much higher yields and therefore at much lower cost than before. Coordinator: Prof Dr Hans-Georg Sahl, Bonn
• Antibiotics are still our most important weapon in the fight against infections. • Without antibiotics, modern advanced medicine would be inconceivable. • Bacteria are becoming increasingly resistant to antibiotics. • The number of new candidate agents in pharmaceutical research departments is small. • For many years now, too few innovative antiinfective drugs have come onto the market.
Science – Translation in focus
ligands have outstanding properties for preventive or therapeutic use against infectious disease. This approach is already in preclinical development and will later be tested in clinical trials.”
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Product Development Unit
Research infrastructures
Advice for the step into a new world
DZIF promotes collaboration between research and the pharmaceutical industry.
The path from a promising scientific discovery to development of a drug or vaccine is long and laborious. After positive research results are achieved, many years elapse before a new medicine or method of treatment is approved – and the abandonment rate is high. To improve the translation of scientific findings into medical products, DZIF has established the TI “Product Development Unit” (PDU). It combines the expertise of two offices: the Office for Scientific and Regulatory Advice of the Paul Ehrlich Institute in Langen and the Translational Project Management Office of the Helmholtz Centre for Infection Research in Braunschweig. Their activities include advising project heads and their teams on the scientific, regulatory and organisational aspects of product development. In collaboration with the project teams, experts in the translational infrastructure PDU draft funding applications, design product profiles and create development and utilisation plans which are then jointly implemented. The regulatory requisites for
the developmental projects are identified and suggestions for realistic solutions developed. The advisors help identify potential industrial partners for joint studies and the subsequent exploitation of acquired property rights. Many consultation meetings were held in 2013 and the experience gained through them was preserved in a database. This will make it easier in future to recognise and overcome hurdles blocking the path to the development of active agents and drugs. For this it is important to include the PDU in the earliest possible product developmental phase. The DZIF unit also provides seminars on special aspects of product development. In 2013, for example, a seminar was held at the Paul Ehrlich Institute on “Due Diligence”, the investigation of a promising development by a buyer such as “Big Pharma”. Coordinator: Prof Dr Klaus Cichutek, Langen
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Clinical Trial Unit
Fostering competitively viable, efficient and high-quality standard ID clinical trials at all DZIF sites is the main objective.
The experts of the TI “Clinical Trial Unit” (DZIF-CTU) are fostering the transfer of findings from basic and clinical research into therapeutic applications. DZIF’s nine specialised infectious disease (ID) clinical trial units (CTUs) provide the platform for testing and evaluating novel clinical compounds and medicinal products within DZIF. The DZIF-CTU Coordinating Office (CO) at the Centre for Clinical Trials, Cologne, forwards feasibility requests to the associated CTUs, coordinates and supports the implementation of a mutual quality management system and manages the centralised, web-based site management system. The CO also supports the CTUs on all matters of conducting clinical trials. The main objective of this TI is enabling competitively viable and efficient performance of ID clinical trials at all DZIF-sites following uniformly high quality standards. This applies to trials with compounds and medicinal products developed within DZIF and to industry-sponsored trials. “In the long term, we want to establish DZIF as pre-
ferred partner for international academic and industrysponsored trials,” states coordinator Prof Oliver Cornely. In 2013 the Coordinating Office introduced a mutual quality management strategy at all DZIF CTUs entailing the implementation of the BMBF-sponsored standard operating procedure templates. “Furthermore, we want to highlight DZIF-CTU´s excellence and visibility in an international setting,” Cornely adds. The CO successfully integrated the DZIF-CTU network in three calls of the European Union (IMI-JU Calls “COMBACTE”, “APC”, and “CARE”), making it part of an international network of clinical trial sites and microbiological laboratories. Within these networks the CTUs will participate in clinical trials focussing on bacterial resistance in collaboration with the industrial partners GlaxoSmithKline, MedImmune and AstraZeneca. Coordinator: Prof Dr Oliver Cornely, Cologne
Research infrastructures
Collaboration with universities and industry
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African Partner Sites
Research infrastructures
Helpful partnership
Joint projects with established African partner institutes.
Many infectious diseases that appear only rarely in Central Europe are endemic and widespread in African countries. Improved collaboration with scientists in Africa is therefore vital if we are to research and effectively combat these diseases. In the TI “African Partner Sites”, DZIF will be intensifying this cooperation by strengthening relationships, some of them long-standing, between various DZIF locations and partners in Africa, as well as coordinating their activities more efficiently. One primary goal is to establish a network between DZIF’s institutes and four established scientific institutions in Ghana, Gabon, Burkina Faso and Tanzania for the purpose of jointly researching malaria, tuberculosis, HIV and so-called neglected diseases. German and African experts are jointly analysing the spread of these diseases – and thereby creating the basis for a better understanding of the pathogens. All findings flow into a database and are thus available to all DZIF researchers. An advantage of this infrastructural unit is that the four partner establishments are located in different areas of Africa, with different environmental conditions and different hereditary risk factors in the population.
One current focus of the TI is a two-year project on fever without source (FWS). Every year, around 200 to 300 children with this symptom are admitted into the study at the hospitals of the four partner institutes. The pilot phase of the project has been concluded successfully and the actual FWS study has already started. Its results will broaden our view on the spectrum of infectious germs in Africa – which will allow us to detect emerging infections more quickly in future. Coordinator: Prof Dr Jürgen May, Hamburg
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Natural Compound Library
A library of bacteria and fungi is to be made available to all DZIF units.
Not all microorganisms make us sick; many are even our allies in the fight against infectious disease. They produce a diversity of substances that inhibit the effects of pathogenic germs on the organism. As a result most antibiotics are made from substances of natural origin. Yet only a few of the countless suitable natural compounds have been researched for their medical usefulness. With the TI “Natural Compound Library”, DZIF has intensified and restructured its research in this field – and is building upon the experience and technical facilities at the Helmholtz Centre for Infection Research (HZI), the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) and the Leibniz Institute DSMZ (German Collection of Microorganisms and Cell Cultures). The aim is to extend the HZI’s existing library of bacteria and fungi and their active compounds, and to make it available to all units of DZIF for antibiotic research and screening. In addition, the natural compound samples will be analysed at the HZI in novel test systems developed by the Department of Chemical Biology. The scientists have obtained numerous natural compounds, predominantly from myxobacteria, which are now being
studied in greater detail. One of the groups of chemical compounds is known as the cystobactamides . These compounds exhibit a broad spectrum of anti-infectious actions which are to be analysed and evaluated in a follow-up project within the TTU “Novel Anti-Infectives”. Since 2013, the scientists have also renewed their focus on fungi. Fungi are an excellent and diverse source of novel antibiotics. The first extracts from these organisms were recently made available within the DZIF network for searching for active compounds. Further interesting samples are expected in 2014, for example extracts from acidobacteria that have been processed at the DSMZ. In the search for potential natural antibiotics, methods employed by researchers of this TI include functional genomics and systems biology. Existing production facilities have been stocked up in order to produce promising substances in ample quantities. As one example, myxobacteria can now be obtained at HZI in fermentation tanks of around 2000-litre capacity. Coordinator: Prof Dr Rolf Müller, Braunschweig/ Saarbrücken
Research infrastructures
Using bacteria and fungi to fight infection
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Biobanking
Research infrastructures
Expanding infrastructure and collections
Biobank standards are being established for the biomaterial collections of the DZIF institutes.
At its institutes in Heidelberg, Munich and HannoverBraunschweig, DZIF is building a platform for biobanks and biobanking technologies. Their focus lies on the standardised recording and quality control of biomaterials as well as novel technologies for entry, storage and processing. “This allows a broad, multi-location use of reliable and comparable samples for basic research and translational research within DZIF,” explains Prof Peter Schirmacher, coordinator of the TI “Biobanking”. Quality-assured collections of tissue samples, liquid samples, infectious pathogens and microbial compound producers are already established at the selected locations. The biobank in Heidelberg collects infectious tissue, which is entered into the records and stored using 2D barcodes. Scanning this code allows rapid, qualityassured recording and traceability of the samples.
The German Collection of Microorganisms and Cell Cultures in Braunschweig has expanded its stock of microorganisms. Samples of the gastroenteritis-causing bacterium Clostridium difficile and more than 60 isolates of intestinal bacteria of mice have been recorded and analysed. The TI “Biobanking” has developed an ethics and privacy policy and expanded the international relationships of DZIF (Infectious Diseases Biobank, London). The infrastructure meeting in Braunschweig largely initiated and organised by the TI served to intensify the collaboration with the other TIs and TTUs. Furthermore, the TI initiated collaboration with the biobank platforms of other German Health Research Centres and coordinated the meetings that were held. Coordinator: Prof Dr Peter Schirmacher, Heidelberg
The Munich team has developed a biobank catalogue, following the European model, for documenting the biomaterial collections of the DZIF institutes. So far, 29 biobanks are registered in this catalogue. For DZIF’s transplant cohort, a separate register database has been set up for the data of patients at risk of infection.
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Bioinformatics
Bioinformatic methods are indispensable in infection research.
Technological advances are ushering in a new era of clinical microbial diagnostics and epidemiological tracing of outbreaks. The genomes of both pathogens and hosts, and the active genes coded within them, can now be fully sequenced within a day. Yet routine use of microbial sequencing in clinics and public health establishments is still a long way off. There is a lack of automated analytical tools for converting the enormous quantities of sequencing data into information that can be translated into new, improved treatment strategies. To exploit bioinformatics fully, researchers need powerful hardware and software tailored to the specific problems as well as skill in handling the bioinformatic tools. To grant all DZIF researchers access to a uniform computing environment with powerful hardware and interpretation pipelines for sequence data, the TI “Bioinformatics” was established. Participants include Gießen University and the Helmholtz Centre for Infection Research in Braunschweig. DZIF Bioinformatics is dedicated to three service areas. These are information transfer, training activities and the establishment of a “Bioinformatics Resource Cen-
tre” (BRC). Synergy effects will be exploited to pass on the existing bioinformatics expertise to partners and to support the DZIF researchers with training courses. Since the establishment of the BRC in 2013, enormous quantities of data can be rapidly and reliably prepared and analysed. The platform www.bioinformatics-platform. dzif.de offers clinicians and associated scientists automated analysis programs: for comparative genomics, mutation analysis, metagenomics and diversity analyses of microbial communities, analyses of host genome and transcriptome datasets, and the illustration of genetic relationships between gene regulatory networks and metabolic pathways. Workshops and training courses have also been held to familiarize DZIF researchers with the new tools. The TI “Bioinformatics” thereby supports the establishment of sequencing in hospitals. This benefits the patient, with the new tools helping to control outbreaks of pathogens and providing a rational basis for curbing antibiotic resistance. Coordinators: Prof Dr Trinad Chakraborty, Gießen; Prof Dr Alice McHardy, Braunschweig
Research infrastructures
Tracking infections with informatics
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DZIF Academy
Promotion of young researchers
Fast track for talented students
The next generation will finally close the divide between research and clinical practice.
Dr Jan-Hendrik Bockmann is a physician and researcher by conviction, yet combining daily hospital work with research is no easy task. “Work at the hospital takes up a lot of your time,” he says. Accordingly, time for research is limited. Bockmann therefore applied for a stipend from the DZIF Academy. It offers clinical physicians the opportunity to advance their career in infection research.
part-time, and has extended eleven more by half a year. “This shows how extensive the fellows’ projects are,” says Cauleen Noël, contact person for the DZIF Academy. The Academy also assists young mothers wishing to return to a research career by awarding maternity stipends covering a large portion of their salary. Three such stipends started at different locations in 2013.
“To apply, you need to find a partner institute within DZIF and work out a draft for a project that you would like to conduct there for one year,” Bockmann recounts. He opted for the Institute of Virology at the Technische Universität München, where he found the ideal conditions for doing research on the hepatitis virus under the direction of Prof Ulrike Protzer. The physician from Hamburg feels the DZIF Clinical Leave Stipend perfectly answers and justifies his wish to concentrate more deeply on research. “I’ve been integrated into a team of scientific colleagues that fosters an active and stimulating exchange of results and ideas,” he comments enthusiastically.
The Academy’s aim is to get young scientists interested in infection research and to enrich this discipline with knowledge direct from hospitals. To this end, students are invited to enrol in doctoral programmes; in spring and autumn schools focussing on scientific or clinical topics, researchers and physicians can also deepen their knowledge and exchange expertise.
Since the beginning of 2013, DZIF has awarded seven Clinical Leave Stipends, of which five are full-time and two
Jan-Hendrik Bockmann already benefits from the Academy. He will be following a two-track career in the future with a double benefit. While practicing as a physician back in Hamburg, he will be able to build upon the latest insights from research. As a researcher, his experience from medical practice will be a continual source of inspiration.
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Collaboration in DZIF
Countless samples serve the research community.
When monitoring the emergence of new infectious diseases, it is of immeasurable value to understand the evolutionary development of pathogens in detail. Only with this knowledge can predictions be made on the potential dangers from new infectious viruses or bacteria, and preventive methods and treatments developed. Within DZIF, scientists from basic research, diagnostics and clinical research get together to work on such acute topics of great importance to our health. One prominent example: In 2013, DZIF researchers of the TTUs “Emerging Infections” and “Hepatitis” discovered a virus in tentmaking bats that is closely related to the hepatitis B virus. It is also capable of infecting humans – but conventional vaccines will not protect against it. These early warning signs are very important because hepatitis B is one of the most widespread infectious diseases of all. It can lead to liver inflammation and cancer. To study this virus, virologists of the TTU “Emerging Infections” at the University Hospital Bonn, members of the TTU “Hepatitis” at Gießen University and researchers from other countries took blood and liver samples from thousands of bats of numerous species from Panama,
Brazil, Gabon, Ghana, Papua New Guinea, Australia and Germany. They tested these for viral DNA of the hepatitis B virus and discovered three different virus strains that are very similar to the human hepatitis B virus. They also discovered that one virus, isolated from the tent-making bat, can infect human liver cells. This was not the case with the other two virus strains. Further tests on this virus, which could be infectious to humans, revealed that the standard vaccination against hepatitis B used around the world does not protect against the virus from the tent-making bat. “This changes a fundamental belief,” says Prof Christian Drosten, Director of the Institute of Virology at University Hospital Bonn. “The question now is whether it will be possible to eradicate hepatitis B worldwide using the conventional vaccine.” PD Dr Dieter Glebe of the National Reference Centre for Hepatitis B and D Viruses adds: “The discovery of new hepatitis B viruses from bats should be a starting point for developing more effective hepatitis B vaccines.”
Collaboration in DZIF
On the trail of the hepatitis B virus
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DZIF Highlights 2013
DZIF Highlights 2013
Step by step against infections
DZIF supports the fifth bi-annual meeting of the Global Virus Network, hosted at Technische Universität München under the leadership of Prof Ulrike Protzer.
International cooperation in the DZIF Biobank: A Memorandum of Understanding is signed with the Infectious Diseases Biobank London.
July DZIF scientists from the Research Center Borstel and Klinikum der Universität München evaluate the Marius Nasta Institute in Bucharest, a new potential DZIF clinical trial unit in eastern Europe.
June Retreat: In June, the DZIF partners get together at Lake Tegernsee to decide their strategy for the future. The Scientific Advisory Board meets for the first time.
January
March DZIF researchers explain how killer T-cells multiply. The scientists publish their results in the journal “Science”.
In the scope of the European “Innovative Medicines Initiative – Joint Undertaking” (IMI-JU), the network project COMBACTE starts. COMBACTE plans clinical trials to counter the developing resistance to antibiotics, with the involvement of DZIF’s Clinical Trial Units. Prof Oliver Cornely, coordinator of the Clinical Trial Unit of DZIF, becomes the German The research coordinator within COMBACTE. areas, infrastrucThe first tures and main office DZIF junior of DZIF commence group starts up operations. in Bonn under the direction of Tanja Schneider.
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December
November September DZIF researchers present their recentlydeveloped potential vaccine against the newly-emerged coronavirus. It is the first vaccine candidate publicised worldwide that could be used as an emergency vaccine in the event of an epidemic in humans.
The first Translational DZIF- School is held in Bad Malente.
Virologist and DZIF researcher Prof Ralf Bartenschlager of Heidelberg University Hospital receives the Lautenschläger Research Prize worth 250,000 euros.
October First DZIF professor: Marylyn Addo answers a call to the University Medical Center Hamburg-Eppendorf (UKE), where she accepts DZIF‘s first W2 professorship. Addo is working on the early detection and combatting of emerging infectious diseases.
The representatives of all commonly established DZIF infrastructures meet for the first time in Braunschweig to discuss their capabilities, requirements and projects.
DZIF Highlights 2013
Prof Mark Brönstrup accepts a W3 professorship for Chemical Biology at HZI, thereby reinforcing DZIF and its Natural Compound Library.
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Science and public
Science and public
Media relations, websites, newsletter: Getting DZIF talked about
Interface to the public: Janna Schmidt and Karola Neubert reinforce DZIF through communication.
Be it MERS, Ebola, malaria or HIV – infectious diseases and how to fight them are topics of great public interest. What are researchers doing against these diseases? How do they ensure their work reaches the patient? And how are all the different research disciplines coordinated to make it happen? From the beginning, DZIF has afforded high priority to maintaining openness and transparency regarding the aims and methods of its translational research. Constant communication with the media is essential The Communications Division commenced work in September 2013. The contacts are Karola Neubert and Janna
Schmidt – two PR officers with long-standing experience in science and commerce. Their task is to strengthen internal and external communication. The division has been busy; the essential basis is constant communication with the media. With more than 200 scientists at locations throughout Germany, the spectrum of exciting and newsworthy topics is very wide. This can be seen from an excerpt of press releases from 2013: First DZIF Professor – Professor Suerbaum is a new member of Academia Europeae – Award for Ralf Bartenschlager – Europe concerned: When antibiotics no longer help; “
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Strong online presence Just as important as proactive media relations is the upkeep and expansion of the DZIF website. It is continuously being updated and filled with life. A new category “DZIF People”, for instance, presents the people behind the excellent research and the creation of the translational infrastructure. The partner website www.infection-research. de highlights worldwide trends in research, provides information on backgrounds and key players, and thereby positions DZIF as the central contact when it comes to infection research. In future, DZIF will be concentrating more strongly on its presence at events and fairs. In the autumn of 2013, for example, the Helmholtz Centre for Infection Research organised the series of events “Milestones in Medicine” supported by DZIF. Around 250 interested visitors came to the event to inform themselves about vaccines, antibiotics and transplants. Internal communication strengthens social cohesion Of critical importance for a virtual association such as DZIF is internal communication. Informing and sharing are key to successful collaboration. An e-mail newsletter therefore keeps everyone up to date with news from DZIF. The first went out at the beginning of 2014.
Science and public
First vaccine against new coronavirus. DZIF has aroused interest in the media with these and many other topics.
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Collaboration with scientific institutions and industry
Collaborations
External collaborations
Good collaboration with external partners strengthens DZIF.
Numerous external collaborations at a national and international level reinforce DZIF’s position as an outstanding institution in the field of infection research.
Collaborations with scientific institutions University of Freiburg The epidemiology and diagnostics of tuberculosis are being researched in a project with the University of Freiburg. One focus is on establishing a diagnostic test (TB Disc) for detecting resistance and for differentiating clinical isolates in various phylogenetic lines. A lab-on-a-disc system is being developed for use in field laboratories, for example at two African partner institutes.
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German Liver Foundation, Hanover The HepNet Study House networks trial centres for hepatitis research and provides a platform for conducting clinical trials. DZIF can make use of infrastructures and cohorts for its projects. Current activities are focussing on hepatitis B, C, D and E. With the German Liver Foundation, a project on hepatic encephalopathy is set to start in 2014. Friedrich-Löffler-Institut, Riems The Friedrich-Löffler-Institut (FLI) is a partner in a collaborative project aimed at the early detection of pathogens transmitted from animals, in particular. This requires blood and tissue samples and nucleic acid preparations from domestic and wild animals, as are available at the FLI. Hans Knöll Institute, Jena The Hans Knöll Institute (HKI) is a leading institute in natural compound research. As an associated partner, it provides DZIF with natural compounds, in particular from fungi. One project is testing the pharmacodynamics of corallopyronin A, a natural product that has already been successfully tested against filariasis pathogens and is currently undergoing preclinical evaluation. The HKI is largely responsible for its biosynthesis. IMI – Innovative Medicines Initiative, Brussels The Clinical Trial Units of DZIF (DZIF-CTUs) have successfully applied to the Innovative Medicines Initiative – Joint Undertaking (IMI-JU) of the European Union. Within the resulting European consortiums (e.g. COMBACTE),
the DZIF-CTUs are involved in trials for combatting bacterial resistance and will be collaborating with the industrial partners GlaxoSmithKline, MedImmune and AstraZeneca. Infectious Diseases BioBank, London Since 2013, a cooperation has existed between the DZIF Biobank and the Infectious Diseases BioBank (IDB) London. The IDB contains, among other things, blood samples from HIV, hepatitis B and hepatitis C patients, as well as patients with methicillin-resistant Staphylococcus aureus infections. Goethe University Frankfurt am Main At the Goethe University Frankfurt am Main, a project focussing on hepatitis is running, in which clinical cohorts are being established. Blood samples taken from patients before therapy or after failed therapy are available to all cooperation partners. The clinical data are being analysed together with the results of a viral and host gene analysis and the phenotypic results. Max Planck Institute for Informatics, Saarbrücken At the MPI for Informatics in Saarbrücken, data from hepatitis C patients treated with new antiviral agents are being gathered as part of a DZIF project (see Goethe University Frankfurt am Main above) that is intended to help in making better predictions of the course of the disease and the response to treatment, and adapting the treatment individually. By sequencing, analysis and interpretation of the patient and viral genes, along with other parameters, it should be possible to predict the course of treatment. In Saarbrücken, the analytical results are being used to develop an online-based tool. Robert Koch Institute, Berlin DZIF is collaborating with the Robert Koch Institute (RKI) in many fields. Three examples: In the field of “emerging infections”, the RKI is supporting the strategic partnership between research institutions, clinics and pharmaceutical companies. Clinical guidelines are being developed within of clinical trials. In HIV research, DZIF can use the new database HIOBs of the RKI.
Collaborations
Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin is a partner in a study on the intelligent use of antibiotics in hospitals. The study is investigating whether targeted intervention regarding use of antibiotics in the hospital or practice influences the frequency of new cases of infections with certain antibiotic-resistant bacteria. A method for monitoring multidrug-resistant organisms is being used, which was developed at Charité with the new module “ATHOS-MRE Surveillance”.
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Medical Center – University of Freiburg In a project with the Medical Center – University of Freiburg on infections of the immunocompromised host, scientists are looking to find genetic factors associated with increased susceptibility to infection. They intend to find biomarkers that allow better infection control. Focus is on fungal infections of immunocompromised patients.
Collaborations
A second DZIF project is looking into more targeted use of antibiotics (see also Charité). University of Münster The University of Münster is a partner in a project aimed at developing new treatment strategies against gastrointestinal infections. In many cases, the antibiotics commonly used nowadays harm the normal gut flora and can lead to complications. In Münster, the scientists are working on preventing the complications associated with EHEC. A second project is working on hospital bugs, and in particular multidrug-resistant Staphylococcus aureus in the nasal region. New lytic phage proteins are being studied for targeted treatment. Their efficiency and specificity will be analysed in Münster.
Collaborations with industry Hyglos GmbH, Bernried The designer-phage proteins currently being developed against Staphylococcus aureus strains in a DZIF project (see University of Münster) are being developed and produced by Hyglos GmbH, Bernried. They are highly soluble and especially stable – an important prerequisite for future drug formulations. Myr GmbH, Burgwedel Together with the University of Heidelberg, an active agent (Myrcludex) is being developed that can prevent hepatitis B viruses from penetrating into cells. Myr GmbH is coordinating the entire project and overseeing the clinical trial. Sanaria Inc., Rockville (USA) At DZIF Tübingen, scientists are developing a human malaria infection model. The disease is being induced under controlled conditions in order to test new active agents. Sanaria Inc. in Rockville, USA, produces malaria parasites for immunisation purposes, which fulfil all the criteria for drug approval. 4SC AG, Martinsried In the TTU “Malaria”, a candidate antimalarial has gone into preclinical development. SC83288 is being tested as an inhibitor in the animal model and further developed in close collaboration with 4SC, which also produces the active agent.
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DZG
DZG
German Health Research Centres
The main objective of the German government‘s health research programme is to develop more effective ways to combat widespread diseases. The groundwork for this has been laid at federal and state level with the establishment of German Health Research Centres as long-term, equal partnerships between non-university research institutes and universities with medical centres. These German Health Research Centres are pooling all of their existing expertise, thereby greatly helping to close knowledge gaps and improve prevention, diagnosis and therapy of the diseases involved. The research policy ensures close collaboration between basic research and clinical research, always specifically oriented to the indications and the patients’ needs. Close networking and the expansion of existing research structures will allow faster transfer of research results into clinical practice (translation). The strategic cooperation of leading scientists in the German Health Research Centres promotes Germany to
a high-ranking scientific location and increases its attractiveness to young scientists in Germany and around the world. 2009 saw the foundation of the “German Centre for Neurodegenerative Diseases” and the “German Centre for Diabetes Research”. Alongside DZIF, the “German Center for Cardiovascular Research”, the “German Consortium for Translational Cancer Research” and the “German Center for Lung Research” were launched in 2012. From the outset, the six German Health Research Centres have collaborated closely in order to share their findings and exploit synergies.
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Organisation and bodies
Facts and figures
Structure of DZIF Commission of Funding Authorities
Executive Board
Scientific Advisory Board
The Commission of Funding Authorities – federal government and respective states (Länder) – decides on important matters of finance, organisation and personnel. The Executive Board and the Managing Director report to the Commission on all funding measures.
The Executive Board represents DZIF externally. It implements the resolutions and tasks assigned by the General Assembly and is responsible for routine administrative affairs.
The association is supported by a Scientific Advisory Board of internationally renowned experts from the field of infection research. The Scientific Advisory Board advises the Executive Board and General Assembly on all scientific and programmerelated matters.
Main Office
Internal Advisory Board
The Main Office is located in Braunschweig and supports the Executive Board in its work. Its duties include organising research initiatives and coordinating DZIF‘s press and public relations activities.
The members of the Internal Council are DZIF scientists representing all areas and locations of the centre. The council advises the Executive Board on all scientific, programme-related and technical matters and performs representative duties.
Thematic Translational Units (TTU)
Translational Infrastructures (TI)
The Thematic Translational Units bundle the research of the centre. Each unit dedicates itself to one pathogen or to one specific problem in infection research.
Strategically aligned translational infection research requires modern infrastructures. These are provided in the form of the Translational Infrastructures, and can be used by all DZIF members.
Emerging Infections
Tuberculosis
Malaria
HIV
Product Development Unit
Clinical Trial Units
Hepatitis
Gastrointestinal Infections
African Partner Sites
Biobanking
Infections of the immunocompromised Host
Healthcare-associated and Antibiotic-resistant bacterial Infections
Natural Compound Library
Bioinformatics
Novel Antiinfectives
DZIF Academy
Partner sites DZIF conducts its research in 32 research establishments at seven locations throughout Germany. For each site, two scientists are appointed to coordinate the collaboration and to advise the Main Office. Various external research partners are also involved in DZIF projects. Bonn-Cologne
Gießen-Marburg-Langen
Hamburg-Lübeck-Borstel
Hannover-Braunschweig
Heidelberg
Munich
Tübingen
Associated Partners
General Assembly The General Assembly is the central decision-making organ of DZIF. It comprises representatives of the member research establishments of DZIF. The General Assembly elects the members of the Executive Board and the Executive Director, and decides on the allocation of funds to the TTUs and TIs.
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Executive Board
Internal Advisory Board
> Prof Dr M. Krönke, Universität und Universitätsklinikum Köln (Chair) > Prof Dr U. Protzer, Technische Universität München und Helmholtz Zentrum München (Vice Chair) > Prof Dr D. Heinz, Helmholtz-Zentrum für Infektionsforschung, Braunschweig
> Prof Dr I. Autenrieth, Universität und Universitätsklinikum Tübingen > Prof Dr K. Cichutek, Paul-Ehrlich-Institut, Langen > Prof Dr C. Drosten, Universität und Universitätsklinikum Bonn > Prof Dr M. Hoelscher, Ludwigs-MaximiliansUniversität München and Klinikum der Universität München > Prof Dr R. Horstmann, Bernhard-Nocht-Institut für Tropenmedizin, Hamburg (Vice Chair) > Prof Dr H.-G. Kräusslich, Universität und Universitätsklinikum Heidelberg (Chair) > Prof Dr T. Schulz, Medizinische Hochschule Hannover > Prof Dr T. Welte, Medizinische Hochschule Hannover
Managing Director > Dr T. Jäger, DZIF e.V.
Scientific Advisory Board > Prof Dr P. Alonso, Universitat de Barcelona, Spain > Prof Dr R. Burger, Robert Koch Institut, Germany > Prof Dr H. Feldmann, National Institute of Allergy and Infectious Diseases, USA > Prof Dr B. B. Finlay, University of British Columbia, Canada > Prof Dr A. Friedrich, Universitair Medisch Centrum Groningen, Netherlands > Prof Dr B. Kampmann (Chair), Imperial College London, United Kingdom > Prof Dr J.-M. Pawlotsky, Université de Paris XII, France > Prof Dr C. Rooney, Baylor College of Medicine, USA > Prof Dr H. J. Schmitt, Johannes Gutenberg Universität Mainz, Germany, and Pfizer Vaccines, France > Prof Dr A. Telenti, Université de Lausanne, Switzerland > Prof Dr S. Ward, Liverpool School of Tropical Medicine, United Kingdom > Prof Dr R. G. Werner, Universität Tübingen, Germany
Facts and figures
Central bodies
42
Hamburg - Lübeck - Borstel
Hannover - Braunschweig
Bonn - Cologne
Gießen - Marburg - Langen
Heidelberg
Tübingen Munich
Partner sites and member establishments
43
Germany-wide infection research Baden-Württemberg
Tübingen has assumed the coordinating role in DZIF for Malaria and Healthcareassociated and Antibiotic-resistant bacterial Infections, and co-coordinators of Gastrointestinal Infections and Novel Antiinfectives are working at this location. The main focus in Tübingen is on the translation of research results into medicine and vaccine development as well as on infection models and epidemiology. Regarding infections caused by antibiotic-resistant, bacterial pathogens, focus is on improving diagnosis and therapy of multiresistant pathogens such as methicillin-resistant Staphylococci (MRSA) and multiresistant gram-negative pathogens (e.g. so-called ESBLs). Heidelberg Spokesperson: Prof Dr Hans-Georg Kräusslich (Heidelberg University) Establishments: German Cancer Research Center in the Helmholtz Association, Heidelberg University, Heidelberg University Hospital
TTU coordination: • Hepatitis (co-coordination) • HIV (coordination) • Infections of the Immunocompromised Host (co-coordination) • Malaria (co-coordination) TI coordination: • Biobanking (coordination) Tübingen Spokesperson: Prof Dr Ingo Autenrieth (University of Tübingen) Establishments: University of Tübingen, Max Planck Institute for Developmental Biology, University Hospital Tübingen TTU coordination: • Gastrointestinal Infections (co-coordination) • Healthcare-associated and Antibioticresistant bacterial Infections (coordination) • Malaria (coordination) • Novel Antiinfectives (co-coordination)
Facts and figures
Heidelberg has assumed coordination of the TTU HIV in DZIF. In order to control HIV infections, DZIF researchers at this location are researching factors of the innate immune system and are identifying sites in the DNA into which the viral DNA can become integrated. Alongside HIV, Heidelberg co-coordinates the TTUs Hepatitis, Malaria and Infections of the Immunocompromised Host. The Heidelberg scientists also coordinate the DZIF-wide translational infrastructure Biobanking, with focus on establishing tissue banks.
Facts and figures
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Bavaria
Hamburg/Schleswig-Holstein
Hessen
The scientists of the Munich DZIF establishments are especially focussed on the immune control of infections and the development of novel therapies. Pathogenspecific immunotherapies (prophylactic or therapeutic) aim at strengthening the body‘s natural defence system so that it can control specific infectious diseases more effectively or even avoid them entirely. Other focuses in Munich are Gastrointestinal Infections, HIV, Hepatitis and Tuberculosis.
The Hamburg-Lübeck-Borstel site combines a unique collection of expertise and infrastructure for studying infectious diseases and emerging infections of national and worldwide relevance. It is involved in clinical, entomological and virological studies. It is the base for medical chemistry for active agent development as well as for the epidemiology of malaria and translational studies on tuberculosis and hepatitis. The TI African Partner Sites is coordinated from here.
Munich Spokesperson: Prof Dr Dirk Busch (Technische Universität München) Establishments: Helmholtz Zentrum München – German Research Center for Environmental Health, Bundeswehr Institute of Microbiology, Klinikum der Universität München, Klinikum rechts der Isar der Technischen Universität München, Ludwig-Maximilians-Universität München, Technische Universität München TTU coordination: • Gastrointestinal Infections (co-coordination) • Hepatitis (co-coordination) • HIV (co-coordination) • Infections of the Immunocompromised Host (coordination) • Tuberculosis (co-coordination) TI coordination: • Biobanking (co-coordination) • DZIF Academy (coordination)
Hamburg - Lübeck - Borstel Spokesperson: Prof Dr Rolf Horstmann (Bernhard Nocht Institute for Tropical Medicine) Establishments: Bernhard Nocht Institute for Tropical Medicine in the Leibniz Association, Research Center Borstel – Leibniz-Center for Medicine and Biosciences, Heinrich Pette Institute – Leibniz Institute for Experimental Virology, Universität Hamburg, University Medical Center Hamburg-Eppendorf, Universität zu Lübeck TTU coordination: • Malaria (co-coordination) • Emerging Infections (co-coordination) • Tuberculosis (coordination) TI coordination: • African Partner Sites (coordination)
In Gießen-Marburg-Langen, DZIF researchers are identifying new active agents and vaccines and producing them in quality-assured production processes for scientific and industrial partners. Research activities are concentrated on developing strategies for combatting new or re-emerging infectious diseases in order to contain outbreaks of new pathogens for example by quick, effective action and rapid vaccine development. Marburg is focusing on viral pathogens, while Gießen is concentrating on bacteria and resistance to antibiotics. Gießen - Marburg - Langen Spokesperson: Prof Dr Trinad Chakraborty (Giessen University) Establishments: Gießen University, Paul Ehrlich Institute Langen, Philipps-Universität Marburg, Mittelhessen University of Applied Sciences TTU coordination: • Healthcare-associated and Antibioticresistant bacterial Infections (co-coordination) • Emerging Infections (coordination) TI coordination: • Bioinformatics (coordination) • Product Development Unit (coordination)
Lower Saxony
North Rhine-Westphalia
Six Lower Saxon partner institutes collaborate within DZIF at the Hannover-Braunschweig location. The TTUs Hepatitis and Gastrointestinal Infections are coordinated from here. The scientists here want, among other things, to improve access to hepatitis therapies and are researching on new diagnostic markers for the course of infection and therapy. Also in the researchers’ sights are new pathogen-specific medicines against pathogens such as EHEC, Helicobacter pylori or salmonellae. This location is coordinating the establishment of the Natural Compound Library, which is available to all DZIF researchers in the search for new medicines.
Bonn-Cologne coordinates the TTU Novel Antiinfectives. The DZIF researchers are also researching into faster and more efficient methods for characterising unknown viral pathogens. Unique in Germany are the patient cohorts for HIV and HCV infections as well as HIV/HCV co-infections. In HIV research, researchers are bringing into translation genetherapy–based strategies for the control and prophylaxis of these infections. This location coordinates the DZIF Clinical Trial Units.
Hannover - Braunschweig Spokesperson: Prof Dr Sebastian Suerbaum (Hannover Medical School) Establishments: Helmholtz Centre for Infection Research, Braunschweig, Leibniz Institute DSMZ – German Collection of Microorganisms and Cell Cultures, Hannover Medical School, University of Veterinary Medicine Hannover, Foundation, Technische Universität Braunschweig, TWINCORE – Centre for Experimental and Clinical Infection Research TTU coordination: • Gastrointestinal Infections (coordination) • Hepatitis (coordination) • Infections of the Immunocompromised Host (co-coordination) TI-Koordination: • Natural Compound Library (coordination) • Biobanking (co-coordination) • Bioinformatics (coordination)
Bonn - Köln Spokesperson: Prof Dr Achim Hörauf (University of Bonn) Establishments: University of Bonn, University Hospital Bonn, University of Cologne, University Hospital Cologne TTU coordination: • Emerging Infections (co-coordination) • HIV (co-coordination) • Healthcare-associated and Antibioticresistant bacterial Infections (co-coordination) • Novel Antiinfectives (coordination) TI coordination: • Clinical Trial Units (coordination)
Facts and figures
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46
Finance
DZIF financial data 2013 2013 expenditure in Euros By partner sites
3+20+1416127 61+35+4
Gießen-Marburg-Langen 1,031,347
Facts and figures
Heidelberg 1,667,005
Munich 2,065,093
Tübingen
Associated Partners 399,108
2,713,025
Hamburg-Lübeck-Borstel 1,891,451
Bonn-Cologne
1,631,168
By type of expenditure
Hannover-Braunschweig
2,128,865
Investments
582,666
Material Expenses 4,746,653
Personnel 8,197,744
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Field of work Emerging Infections
Grants from government and Länder in Euros Euros 1,242,422
Land
Euros
Baden-Württemberg
329,817
Tuberculosis
527,467
Bavaria
203,549
Malaria
897,476
Hamburg
112,935
HIV
581,677
Hessen
Hepatitis Gastrointestinal Infections Infections of the immunocompromised Host Healthcare-associated and Antibioticresistant bacterial Infections Novel Antiinfectives
1,181,532 856,952 1,575,547 775,670 1,377,021
Product Development Unit
340,493
Clinical Trial Unit
220,152
African Partner Sites
242,612
Biobanking
553,749
Natural Compound Library
169,439
Bioinformatics
219,216
DZIF Academy
1,161,421
Administration
1,604,218
Total
13,527,063
The expenditure of the German Center for Infection Research in 2013 was around 13.5 million euros. 98 collaborative projects and 32 stipends were funded within DZIF in 2013. The majority of funding came from Federal Government funds (90%) and from Länder funds (10%). Only departmental research projects of the federal R&D institutions are fully funded by Germany’s Federal Ministries. Funding Management at the Helmholtz Centre for Infection Research in Braunschweig forwards the Federal funds to the DZIF partner institutes to support their projects. Expenditure was reported by the partners in their interim statements for 2013 and audited by Funding Management.
75,496
Lower Saxony
271,302
North Rhine-Westphalia
212,887
Schleswig-Holstein
76,210
Financial Contributions from Associated Partners
38,366
Federal Government
12,206,500
Total
13,527,063
Facts and figures
By field of work
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Personnel and awards
Employees of DZIF Full-time equivalent by professional group
1+25+513241715 Professor 0.3
Other 21.5
PhD/MD Student
Facts and figures
23.8
Postdoc 35.9
Total: 142.1
Junior Group Head 7.5 Physician
TA/Study Nurse 34.7
18.4
Full-time equivalent corresponds to a full-time position of the entire fiscal year.
Number of employees by professional group and gender Professional Groups
Men
Women
Total
Professor
0
1
1
Junior Group Head
15
2
17
Physician
19
18
37
Postdoc
36
51
87
PhD/MD Student
33
52
85
TA/Study Nurse
12
62
74
Other
21
36
57
Total
136
222
358
DZIF recruited 17 employees from abroad and assisted nine mothers on their return from maternity leave.
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Laureates
Awards
Prof Dr Ralf Bartenschlager Heidelberg University Hospital
Lautenschläger Research Prize of Heidelberg University
Yi Chai Helmholtz Centre for Infection Research
Chinese Government Award 2013 For Outstanding Self-Financed Students Abroad of the China Scholarship Council
PD Dr Sandra Ciesek Hannover Medical School
2013 Yael Prize of the German Association for the Study of the Liver (GASL)
Prof Dr Petra Dersch Helmholtz Centre for Infection Research
2013 Main Prize of the German Society for Hygiene and Microbiology (DGHM)
Dr Jan Felix Drexler University of Bonn
Heine-Medin Award of the European Society for Clinical Virology
PD Dr Thomas von Hahn Hannover Medical School
2013 Rising Stars Award of United European Gastroenterology
Prof Dr Gunther Hartmann University of Bonn
Selection into the German National Academy of Sciences Leopoldina
Thomas Hoffmann Helmholtz Centre for Infection Research
2013 Poster Prize at the 25th European Conference on Natural Products of DECHEMA
Liujie Huo Helmholtz Centre for Infection Research
2013 Young Scientist Meeting Grant of the Federation of European Microbiological Societies
Liujie Huo Helmholtz Centre for Infection Research
Chinese Government Award 2013 For Outstanding Self-Financed Students Abroad of the China Scholarship Council
Prof Dr Helge Karch University of Münster
2013 Robert Koch Prize for Hospital Hygiene and Infection Prevention
Prof Dr Helge Karch University of Münster
2013 Research Award of the University of Münster
Dr Benno Kreuels University Medical Center Hamburg-Eppendorf
Award for second-best lecture of the German Tropical Medicine Society (DGT)
Prof Dr Dr h.c. Christoph Lange Research Center Borstel
Awarded honorary doctorate by Moldova State University, Chisinau, Moldova
Prof Dr Sebastian Suerbaum Hannover Medical School
Selection into the European Academy of Sciences Academia Europaea
Facts and figures
Awards and commendations
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Publications
Scientific achievements 2013 1. Abass E, Bollig N, Reinhard K, Camara B, Mansour D, Visekruna A, Lohoff M, Steinhoff U (2013) rKLO8, a Novel Leishmania donovani – Derived Recombinant Immunodominant Protein for Sensitive Detection of Visceral Leishmaniasis in Sudan. PLOS Negl Trop Dis, 7(7):e2322
Publications
2. Aburizaiza AS, Mattes FM, Azhar EI, Hassan AM, Memish ZA, Muth D, Meyer B, Lattwein E, Müller MA, Drosten C (2014) Investigation of anti-middle East respiratory syndrome antibodies in blood donors and slaughterhouse workers in Jeddah and Makkah, Saudi Arabia, fall 2012. J Infect Dis, 209(2):243-6 (Epub 2013)
10. Andreu N, Zelmer A, Sampson S L, Ikeh M, Bancroft GJ, Schaible UE, Wiles S, Robertson BD (2013) Rapid in vivo assessment of drug efficacy against Mycobacterium tuberculosis using an improved firefly luciferase. J Antimicrob Chemother, 68(9):2118-27 11. Angenvoort J, Brault AC, Bowen RA, Groschup MH (2013) West Nile viral infection of equids. Vet Microbiol, 167(1-2):168-80 12. Bartenschlager R, Lohmann V, Penin F (2013) The molecular and structural basis of advanced antiviral therapy for hepatitis C virus infection. Nat Rev Microbiol, 11(7):482-496
3. Adlhoch C, Kaiser M, Kingsley MT, Schwarz NG, Ulrich M, de Paula VS, Ehlers J, Löwa A, Daniel AM, Poppert S, Schmidt-Chanasit J, Ellerbrok H (2013) Porcine hokovirus in domestic pigs, Cameroon. Emerg Infect Dis, 19(12):2060-2962
13. Beck J, Echtenacher B, Ebel F (2013) Woronin bodies, their impact on stress resistance and virulence of the pathogenic mould Aspergillus fumigatus and their anchoring at the septal pore of filamentous Ascomycota. Mol Microbiol, 89(5):857-71
4. Al Rushood M, McCusker C, Mazer B, Alizadehfar R, Grimbacher B, Depner M, BenShoshan M (2013) Autosomal Dominant Cases of Chronic Mucocutaneous Candidiasis Segregates with Mutations of Signal Transducer and Activator of Transcription 1, But Not of Toll-Like Receptor 3. J Pediatr, 163(1):277-9
14. Becker N, Geier M, Balczun C, Bradersen U, Huber K, Kiel E, Krüger A, Lühken R, Orendt C, Plenge-Böning A, Rose A, Schaub GA, Tannich E (2013) Repeated introduction of Aedes albopictus into Germany, July to October 2012. Parasitol Res, 112(4):1787-1790
5. Alduina R, Gallo G, Renzone G, Weber T, Scaloni A, Puglia AM (2014) Novel Amycolatopsis balhimycina biochemical abilities unveiled by proteomics. FEMS Microbiol Lett, 351:209-15 (Epub 2013) 6. Aleksic E, Merker M, Cox H, Reiher B, Sekawi Z, Hearps AC, Ryan CE, Lee AV, Goursaud R, Malau C, O‘Connor J, Cherry CL, Niemann S, Crowe SM (2013) First molecular epidemiology study of Mycobacterium tuberculosis in Kiribati. PLOS ONE, 8(1):e55423 7. Allix-Béguec C, Wahl C, Hanekom M, Nikolayevskyy V, Drobniewski F, Maeda S, CamposHerrero I, Mokrousov I, Niemann S, Kontsevaya I, Rastogi N, Samper S, Sng LH, Warren RM, Supply P (2013) Proposal of a consensus set of hypervariable mycobacterial interspersed repetitive-unitvariable-number tandem-repeat loci for subtyping of Mycobacterium tuberculosis Beijing isolates. J Clin Microbiol, 52(1):164-72 8. Allweiss L, Volz T, Lütgehetmann M, Giersch K, Bornscheuer T, Lohse AW, Petersen J, Ma H, Klumpp K, Fletcher SP, Dandri M (2014) Immune cell responses are not required to induce substantial hepatitis B virus antigen decline during pegylated interferon-alpha administration. J Hepatol, 60(3):500-7 (Epub 2013) 9. Ameres S, Mautner J, Schlott F, Neuenhahn M, Busch DH, Plachter B, Moosmann A (2013) Presentation of an immunodominant immediate-early CD8+ T cell epitope resists human cytomegalovirus immunoevasion. PLOS Pathogens, 9(5):e1003383
15. Beggel B, Neumann-Fraune M, Kaiser R, Verheyen J, Lengauer T (2013) Inferring short-range linkage information from sequencing chromatograms. PLOS ONE, 8(12):e81687 16. Bierbaum G, Sahl HG (2014) The search for new anti-infective drugs: untapped resources and strategies. Int J Med Microbiol, 304(1):1-2 (Epub 2013 Oct 11)
21. Borchers S, Ogonek J, Varanasi P, Tischer S, Bremm M, Eiz-Vesper B, Koehl U, Weissinger EM (2014) Multimer monitoring of CMV-specific T cells in research and in clinical applications. (Review) Diagn Microbiol Infect Dis, 78(3):201-212 (Epub 2013) 22. Borchers S, Weissinger EM, Pabst B, Ganzenmueller T, Dammann E, Luther S, Diedrich H, Ganser A, Stadler M (2013) Expansion of recipientderived antiviral T cells may influence donor chimerism after allogeneic stem cell transplantation. Transpl Infect Dis, 15(6):627-33 23. Borst EM, Kleine-Albers J, Gabaev I, Babic M, Wagner K, Binz A, Degenhardt I, Kalesse M, Jonjic S, Bauerfeind R, Messerle M (2013) The human cytomegalovirus UL51 protein is essential for viral genome cleavage-packaging and interacts with the terminase subunits pUL56 and pUL89. J Virol, 87(3):1720-32 24. Borst EM, Ständker L, Wagner K, Schulz TF, Forssmann WG, Messerle M (2013) A peptide inhibitor of cytomegalovirus infection from human hemofiltrate. Antimicrob Agents Chemother, 57(10):4751-60 25. Bryant JM, Harris SR, Parkhill J, Dawson R, Diacon AH, van Helden P, Pym A, Mahayiddin AA, Chuchottaworn C, Sanne IM, Louw C, Boeree MJ, Hoelscher M, McHugh TD, Bateson AL, Hunt RD, Mwaigwisya S, Wright L, Gillespie SH, Bentley SD (2013) Whole-genome sequencing to establish relapse or re-infection with Mycobacterium tuberculosis: a retrospective observational study. Lancet Respir Med, 1(10):786-792
17. Bindt C, Guo N, Bonle MT, Appiah-Poku J, Hinz R, Barthel D, Schoppen S, Feldt T, Barkmann C, Koffi M, Loag W, Nguah SB, Eberhardt KA, Tagbor H, N‘goran E, Ehrhardt S (2013) International CDS Study Group. No association between antenatal common mental disorders in low-obstretic risk woman and adverse birth outcomes in their offspring: results from the CDS study in Ghana and Cote D’Ivoire. PLOS ONE, 8:e80711
26. Buchholz U, Müller MA, Nitsche A, Sanewski A, Wevering N, Bauer-Balci T, Bonin F, Drosten C, Schweiger B, Wolff T, Muth D, Meyer B, Buda S, Krause G, Schaade L, Haas W (2013) Contact investigation of a case of human novel coronavirus infection treated in a German hospital, OctoberNovember 2012. Euro Surveill, 18(8)
18. Blin K, Medema MH, Kazempour D, Fischbach MA, Breitling R, Takano E, Weber T (2013) antiSMASH 2.0 – a versatile platform for genome mining of secondary metabolite producers. Nucl Acids Res, 41,W204-W212
27. Buchholz VR, Flossdorf M, Hensel I, Kretschmer L, Weissbrich B, Gräf P, Verschoor A, Schiemann M, Höfer T, Busch DH (2013) Disparate individual fates compose robust CD8+ T cell immunity. Science, 340(6132):630-5
19. Bogner JR, Kutaiman A, Esguerra-Alcalen M, Heldner S, Arvis P (2013) Moxifloxacin in complicated skin and skin structure infections (cSSSIs): A prospective, international, non-interventional, observational study. Adv Ther, 30(6):630-43
28. Buchholz VR, Gräf P, Busch DH (2013) The smallest unit: effector and memory CD8+ T cell differentiation on the single cell level. Front Immunol, 4:31
20. Bonsor DA, Weiss E, Iosub-Amir A, Reingewertz TH, Chen TW, Haas R, Friedler A, Fischer W, Sundberg EJ (2013) Characterization of the Translocationcompetent Complex between the Helicobacter pylori Oncogenic Protein CagA and the Accessory Protein CagF. J Biol Chem, 288(46):32897-32909
29. Bunse CE, Borchers S, Varanasi PR, Tischer S, Figueiredo C, Immenschuh S, Kalinke U, Koehl U, Goudeva L, Maecker-Kolhoff B, Ganser A, Blasczyk R, Maecker-Kolhoff B, Weissinger EM, Eiz-Vesper B (2013) Impaired functionality of antiviral T cells in G-CSF mobilized stem cell donors: Implications for the selection of CTL donor. PLOS ONE, 8(12):e77925
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31. Chegou NN, Heyckendorf J, Walzl G, Lange C, Ruhwald M (2014) Beyond the IFN-γ horizon: Biomarkers for immunodiagnosis of infection with M. tuberculosis. Eur Respir J, 43(5):1472-86 (Epub 2013) 32. Ching W, Koyuncu E, Singh S, Arbelo-Roman C, Hartl B, Kremmer E, Speiseder T, Meier C, Dobner T (2013) A Ubiquitin-specific Protease Possesses a Decisive Role for Adenovirus Replication and Oncogene-mediated Transformation. PLOS Pathogens, 9(3):e1003273, 1-18 33. Comas I, Coscolla M, Luo T, Borrell S, Holt KE, Kato-Maeda M, Parkhill J, Malla B, Berg S, Thwaites G, Yeboah-Manu D, Bothamley G, Mei J, Wei L, Bentley S, Harris SR, Niemann S, Diel R, Aseffa A, Gao Q, Young D, Gagneux S (2013) Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans. Nat Genet, 45(10):1176-82 34. Corman VM, Eickmann M, Landt O, Bleicker T, Brünink S, Eschbach-Bludau M, Matrosovich M, Becker S, Drosten C (2013) Specific detection by real-time reverse-transcription PCR assays of a novel avian influenza A(H7N9) strain associated with human spillover infections in China. Euro Surveill, 18(16):20461 35. Corman VM, Kallies R, Philipps H, Göpner G, Müller MA, Eckerle I, Brünink S, Drosten C, Drexler JF (2014) Characterization of a novel betacoronavirus related to middle East respiratory syndrome coronavirus in European hedgehogs. J Virol, 88(1):717-24 (Epub 2013) 36. Dammermann W, Schipper P, Ullrich S, Fraedrich K, Schulze Zur Wiesch J, Fründt T, Tiegs G, Lohse A, Lüth S (2013) Increased expression of complement regulators CD55 and CD59 on peripheral blood cells in patients with EAHEC O104:H4 infection. PLOS ONE, 8(9):e74880 37. de Groot RJ, Baker SC, Baric RS, Brown CS, Drosten C, Enjuanes L, Fouchier RA, Galiano M, Gorbalenya AE, Memish ZA, Perlman S, Poon LL, Snijder EJ, Stephens GM, Woo PC, Zaki AM, Zambon M, Ziebuhr J (2013) Middle East respiratory syndrome coronavirus (MERS-CoV): announcement of the Coronavirus Study Group. J Virol, 87(14):7790-92 38. de Paula VS, Wiele M, Mbunkah AH, Daniel AM, Kingsley MT, Schmidt-Chanasit J (2013) Hepatitis E virus genotype 3 strains in domestic pigs, Cameroon. Emerg Infect Dis, 19(4):666-668
39. Deest M, Westhaus S, Steinmann E, Manns MP, von Hahn T, Ciesek S (2014) Impact of single nucleotide polymorphisms in the essential HCV entry factor CD81 on HCV infectivity and neutralization. Antiviral Res, 101:37-44 (Epub 2013) 40. Diel R, Loddenkemper R, Zellweger JP, Sotgiu G, D‘Ambrosio L, Centis R, van der Werf MJ, Dara M, Detjen A, Gondrie P, Reichman L, Blasi F, Migliori GB; European Forum for TB Innovation (2013) Old ideas to innovate tuberculosis control: preventive treatment to achieve elimination. Eur Respir J, 42(3):785-801 41. Dill T, Dobler G, Saathoff E, Clowes P, Kroidl I, Ntinginya E, Machibya H, Maboko L, Löscher T, Hoelscher M, Heinrich N (2013) High Seroprevalence for Typhus Group Rickettsiae in Mbeya Region, Southwestern Tanzania, is associated with Sparse Vegetation and Proximity to a Highway. Emerg Infect Dis, 19(2):317-20 42. Dössinger G, Bunse M, Bet J, Albrecht J, Paszkiewicz PJ, Weißbrich B, Schiedewitz I, Henkel L, Schiemann M, Neuenhahn M, Uckert W, Busch DH (2013) MHC multimer-guided and cell culture-independent isolation of functional T cell receptors from single cells facilitates TCR identification for immunotherapy. PLOS ONE, 8(4):e61384 43. Drexler JF, Corman VM, Müller MA, Lukashev AN, Gmyl A, Coutard B, Adam A, Ritz D, Leijten LM, van Riel D, Kallies R, Klose SM, Gloza-Rausch F, Binger T, Annan A, Adu-Sarkodie Y, Oppong S, Bourgarel M, Rupp D, Hoffmann B, Schlegel M, Kümmerer BM, Krüger DH, Schmidt-Chanasit J, Setién AA, Cottontail VM, Hemachudha T, Wacharapluesadee S, Osterrieder K, Bartenschlager R, Matthee S, Beer M, Kuiken T, Reusken C, Leroy EM, Ulrich RG, Drosten C (2013) Evidence for novel hepaciviruses in rodents. PLOS Pathog, 9(6):e1003438 44. Drexler JF, Geipel A, König A, Corman VM, van Riel D, Leijten LM, Bremer CM, Rasche A, Cottontail VM, Maganga GD, Schlegel M, Müller MA, Adam A, Klose SM, Carneiro AJ, Stöcker A, Franke CR, Gloza-Rausch F, Geyer J, Annan A, AduSarkodie Y, Oppong S, Binger T, Vallo P, Tschapka M, Ulrich RG, Gerlich WH, Leroy E, Kuiken T, Glebe D, Drosten C (2013) Bats carry pathogenic hepadnaviruses antigenically related to hepatitis B virus and capable of infecting human hepatocytes. Proc Natl Acad Sci USA, 110(40):16151-6 45. Drosten C (2013) Is MERS another SARS? Lancet Infect Dis, 13(9):727-8 46. Drosten C, Seilmaier M, Corman VM, Hartmann W, Scheible G, Sack S, Guggemos W, Kallies R, Muth D, Junglen S, Müller MA, Haas W, Guberina H, Röhnisch T, Schmid-Wendtner M, Aldabbagh S, Dittmer U, Gold H, Graf P, Bonin F, Rambaut A, Wendtner CM (2013) Clinical features and virological analysis of a case of Middle East respiratory syndrome coronavirus infection. Lancet Infect Dis, 13(9):745-51
47. Ehren K, Hertenstein C, Kümmerle T, Vehreschild JJ, Fischer J, Gillor D, Wyen C, Lehmann C, Cornely OA, Jung N, Gravemann S, Platten M, Wasmuth JC, Rockstroh JK, Boesecke C, Schwarze-Zander C, Fätkenheuer G (2014) Causes of death in HIV-infected patients from the Cologne-Bonn cohort. Infection, 42(1):135-40 (Epub 2013) 48. Elgaher WAM, Fruth M, Groh M, Haupenthal J, Hartmann RW (2014) Expanding the scaffold for bacterial RNA polymerase inhibitors: design, synthesis and structure–activity relationships of ureidoheterocyclic- carboxylic acids. RSC Advances, 4,2177-2194 49. Esser-Nobis K, Romero-Brey I, Ganten TM, Gouttenoire J, Harak C, Klein R, Schemmer P, Binder M, Schnitzler P, Moradpour D, Bartenschlager R, Polyak SJ, Stremmel W, Penin F, Eisenbach C, Lohmann V (2013) Analysis of hepatitis C virus resistance to silibinin in vitro and in vivo points to a novel mechanism involving nonstructural protein 4B. Hepatology, 57(3):953-963 50. Felder S, Dreisigacker S, Kehraus S, Neu E, Bierbaum G, Wright PR, Menche D, Schäberle TF, König GM (2013) Salimabromide: Unexpected Chemistry from the Obligate Marine Myxobacterium Enhygromyxa salina. Chemistry – A European Journal, 19(28):9319-9324 51. Felder S, Kehraus S, Neu E, Bierbaum G, Schäberle TF, König GM (2013) Salimyxins and Enhygrolides: Antibiotic, Sponge-Related Metabolites from the Obligate Marine Myxobacterium Enhygromyxa salina. ChemBioChem, 14(11):1363-1371 52. Feuerriegel S, Köser CU, Richter E, Niemann S (2013) Mycobacterium canettii is intrinsically resistant to both pyrazinamide and pyrazinoic acid. J Antimicrob Chemother, 68(6):1439-40 53. Fomsgaard A, Fertner ME, Essbauer S, Nielsen AY, Frey S, Lindblom P, Lindgren PE, Bødker R, Weidmann M, Dobler G (2013) Tick-borne encephalitis virus, Zealand, Denmark, 2011. Emerg Infect Dis, 19(7):1171-3 54. Formichella L, Romberg L, Bolz C, Vieth M, Geppert M, Göttner G, Nölting C, Walter D, Schepp W, Schneider A, Ulm K, Wolf P, Busch DH, Soutschek E, Gerhard M(2013) A Novel Line Immunoassay Based on Recombinant Virulence Factors Enables Highly Specific and Sensitive Serologic Diagnosis of Helicobacter pylori Infection. Clin Vaccine Immunol, 20(11):1703-1710 55. Frangoulidis D, Splettstoesser WD, Landt O, Dehnhardt J, Henning K, Hilbert A, Bauer T, Antwerpen M, Meyer H, Walter MC, Knobloch JK (2013) Microevolution of the chromosomal region of acute disease antigen A (adaA) in the query (Q) fever agent Coxiella burnettii. PLOS ONE, 8(1):e53440
Publications
30. Cebula M, Ochel A, Hillebrand Z, Pils MC, Schirmbeck R, Hauser H, Wirth D (2013) An inducible transgenic mouse model for immune mediated hepatitis showing clearance of antigen expressing hepatocytes by CD8+ T cells. PLOS ONE, 8(7):e68720
Publications
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56. Frey S, Essbauer S, Zöller G, Klempa B, Weidmann M, Dobler G, Pfeffer M (2013) Complete Genome Sequence of Tick-Borne Encephalitis Virus Strain A104 Isolated from a Yellow-Necked Mouse (Apodemus flavicollis) in Austria. Genome Announcements, 1(4):e00564-13
64. Garigliany MM, Marlier D, Tenner-Racz K, Eiden M, Cassart D, Gandar F, Beer M, SchmidtChanasit J, Desmecht D (2014) Detection of Usutu virus in a bull- finch (Pyrrhula pyrrhula) and a great spotted woodpecker (Dendrocopos major) in northwest Europe. Vet J, 199(1):191-3 (Epub 2013)
73. Gustems M, Woellmer A, Rothbauer U, Eck SH, Wieland T, Lutter D, Hammerschmidt W (2014) c-Jun/c-Fos heterodimers regulate cellular genes via a newly identified class of methylated DNA sequence motifs. Nucleic Acids Res, 42(5):30593072 (Epub 2013)
57. Frickmann H, Dekker D, Boahen K, Acquah S, Sarpong N, Adu-Sarkodie Y, Schwarz NG, May J, Marks F, Poppert S, Wiemer DF, Hagen RM (2013) Increased detection of invasive enteropathogenic bacteria in pre-incubated blood culture materials by real-time PCR in comparison with automated incubation in Sub-Saharan Africa. Scand J Infect Dis, 45(8):616-22
65. Giersch K, Helbig M, Volz T, Allweiss L, Mancke LV, Lohse AW, Polywka S, Pollok JM, Petersen J, Taylor J, Dandri M, Lütgehetmann M (2014) Persistent hepatitis D virus mono-infection in humanized mice is efficiently converted by hepatitis B virus to a productive co-infection. J Hepatol, 60(3):538-44 (Epub 2013)
74. Guo N, Bindt C, Te Bonle M, Appiah-Poku J, Hinz R, Barthel D, Koffi M, Posdzich S, Deymann S, Barkmann C, Schlüter L, Jaeger A, Blay Nguah S, Eberhardt KA, N‘goran E, Tagbor H, Ehrhardt S for the International CDS Study Group (2013) Association of antepartum and postpartum depression in Ghanaian and Ivorian women with febrile illness in their offspring: A prospective birth cohort study. Am J Epidemiol, 178(9):1394-402
58. Frickmann H, Hänle A, Essig A, Dekker D, Boahen K, Acquah S, Sarpong N, Adu-Sarkodie Y, Schwarz NG, May J, Marks F, Hagen RM, Poppert S (2013) Fluorescence in situ hybridization (FISH) for rapid identification of Salmonella spp. from agar and blood culture broth--an option for the tropics? Int J Med Microbiol, 303(5):277-84 59. Frickmann H, Schwarz NG, Girmann M, Hagen RM, Poppert S, Crusius S, Podbielski A, Heriniaina JN, Razafindrabe T, Rakotondrainiarivelo JP, May J, Rakotozandrindrainy R (2013) Serological survey on HIV and Syphilis in pregnant women in Madagascar. Trop Med Int Health, 18(1):35-9 60. Frickmann H*, Schwarz NG*, Holtherm HU, Maassen W, Vorderwulbecke F, Erkens K, Fischer M, Morwinsky T, Hagen RM, *contributed equally (2013) Compliance with antimalarial chemoprophylaxis in German soldiers: a 6-year survey. Infection, 41(2):311-320 61. Frickmann H, Tenner-Racz K, Eggert P, Schwarz NG, Poppert S, Tannich E, Hagen RM (2013) Influence of parasite density and sample storage time on the reliability of Entamoeba histolytica-specific PCR from formalin-fixed and paraffin-embedded tissues. Diagn Mol Pathol, 22(4):236-244 62. Friedrich SO, Rachow A, Saathoff E, Singh K, Mangu CD, Dawson R, Phillips PP, Venter A, Bateson A, Boehme CC, Heinrich N, Hunt RD, Boeree MJ, Zumla A, McHugh TD, Gillespie SH, Diacon AH, Hoelscher M (2013) Assessment of the sensitivity and specificity of Xpert MTB/RIF assay as an early sputum biomarker of response to tuberculosis treatment.Lancet Respir Med, 1(6):462-470 63. Gabriel M, Emmerich P, Frank C, Fiedler M, Rashidi-Alavijeh J, Jochum C, Günther S, Auerhammer K, Rupprecht HJ, Blank RT, Sacher N, Pertzborn L, Stark K, Schrauzer T, SchmidtChanasit J (2013) Increase in West Nile virus infections imported to Germany in 2012. J Clin Virol, 58(3):587-589
66. Glässner A, Eisenhardt M, Kokordelis P, Krämer B, Wolter F, Nischalke HD, Boesecke C, Sauerbruch T, Rockstroh JK, Spengler U, Nattermann J (2013) Impaired CD4* T cell stimulation of NK cell anti-fibrotic activity may contribute to accelerated liver fibrosis progression in HIV/HCV patients. J Hepatol, 59(3):427-33 67. Glebe D, Bremer (2013) The Molecular Virology of Hepatitis B Virus. Semin Liver Dis, 33(2):103-12 68. Greil J, Rausch T, Giese T, Bandapalli OR, Daniel V, Bekeredjian-Ding I, Stutz AM, Drees C, Roth S, Ruland J, Korbel JO, Kulozik AE (2013) Whole-exome sequencing links caspase recruitment domain 11 (CARD11) inactivation to severe combined immunodeficiency. J Allergy Clin Immunol, 131(5):1376-1383 69. Gronbach K, Flade I, Holst O, Lindner B, Ruscheweyh HJ, Wittmann A, Menz S, Schwiertz A, Adam P, Stecher B, Josenhans C, Suerbaum S, Gruber AD, Kulik A, Huson D, Autenrieth IB, Frick JS (2014) Endotoxicity of lipopolysaccharide as a determinant of T-cell-mediated colitis induction in mice. Gastroenterology, 146(3):765-775 (Epub 2013) 70. Gruber I, Heudorf U, Werner G, Pfeifer Y, Imirzalioglu C, Ackermann H, Brandt C, Besier S, Wichelhaus TA (2013) Multidrug-resistant bacteria in geriatric clinics, nursing homes, and ambulant care-prevalence and risk factors. Int J Med Microbiol, 303(8):405-9 71. Guenther S, Wuttke J, Bethe A, Vojtech J, Schaufler K, Semmler T, Ulrich RG, Wieler LH, Ewers C (2013) Is fecal carriage of extendedspectrum-β-lactamase-pro-ducing Escherichia coli in urban rats a risk for public health? Antimicrob Agents Chemother, 57(5):2424-2425 72. Gupta M, Miller CJ, Baker JV, Lazar J, Bogner JR, Calmy A, Soliman EZ, Neaton JD; INSIGHT SMART Study Group (2013) Biomarkers and electrocardiographic evidence of myocardial ischemia in patients with human immunodeficiency virus infection. Am J Cardiol, 111(5):760-4
75. Haas CS, Lehne W, Muck P, Boehm A, Rupp J, Steinhoff J, Lehnert H (2013) Acute kidney injury and thrombocytopenic fever – consider the infrequent causes. Am J Emerg Med, 31(2):441.e5-9 76. Hagen RM, Wulff B, Loderstaedt U, Fengler I, Frickmann H, Schwarz NG, Polywka S (2013) Is rapid hepatitis C virus testing from corpses a screening option for index persons who have died after mass-casualty incidents in high-prevalence settings in the field? J R Army Med Corps, doi:10.1136/ jramc-2013-000133 77. Hammamy MZ, Haase C, Hammami M, Hilgenfeld R, Steinmetzer T (2013) Development and characterization of new peptidomimetic inhibitors of the West Nile virus NS2B-NS3. Chem Med Chem, 8(2):231-41 78. Hantz S, Cotin S, Borst E, Couvreux A, Salmier A, Garrigue I, Merville P, Mengelle C, Attal M, Messerle M, Alain S (2013) Novel DNA polymerase mutations conferring cytomegalovirus resistance: input of BAC-recombinant phenotyping and 3D model. Antiviral Res, 98(1):130-4 79. Hauck D, Joachim I, Frommeyer B, Varrot A, Philipp B, Möller HM, Imberty A, Exner TE, Titz A (2013) Discovery of Two Classes of Potent Glycomimetic Inhibitors of Pseudomonas aeruginosa LecB with Distinct Binding Modes. ACS Chem Biol, 8(8):1775–1784 80. Hauswaldt S, Nitschke M, Sayk F, Solbach W, Knobloch JK (2013) Lessons Learned from Outbreaks of Shiga Toxin Producing Escherichia coli. Curr Infect Dis Rep, 15(1):4-9 81. Heimann SM, Cornely OA, Vehreschild MJ, Glossmann J, Kochanek M, Kreuzer KA, Hallek M, Vehreschild JJ (2014) Treatment cost development of patients undergoing remission induction chemotherapy: a pharma coeconomic analysis before and after introduction of posaconazole prophylaxis. Mycoses, 57(2):90-7 (Epub 2013)
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91. Jabara HH, Ohsumi T, Chou J, Massaad MJ, Benson H, Megarbane A, Chouery E, Mikhael R, Gorka O, Gewies A, Portales P, Nakayama T, Hosokawa H, Revy P, Herrod H, Le Deist F, Lefranc G, Ruland J, Geha RS (2013) A homozygous mucosaassociated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency. J Allergy Clin Immunol, 132(1):151-158
83. Hilgenfeld R, Peiris M (2013) From SARS to MERS: 10 years of research on highly pathogenic human coronaviruses. Antiviral Res, 100(1):286-295
92. Jafari C, Ernst M, Kalsdorf B, Lange C (2013) Comparison of molecular and immunological methods for the rapid diagnosis of smear-negative tuberculosis. Int J Tuberc Lung Dis, 17(11):1459-65
84. Hitkova I, Yuan G, Anderl F, Gerhard M, Kirchner T, Reu S, Röcken C, Schäfer C, Schmid RM, Vogelmann R, Ebert MP, Burgermeister E (2013) Caveolin-1 protects B6129 mice against Helicobacter pylori gastritis. PLOS Pathogens, 9(4):e1003251 85. Hoffmann J, Boehm C, Himmelsbach K, Donnerhak C, Roettger H, Weiss TS, Ploen D, Hildt E (2013) Identification of α-taxilin as an essential factor for the life cycle of hepatitis B virus. J Hepatol, 59(5):934-41 86. Hoffmann C, Kohrs F, Sabranski M, Wolf E, Jaeger H, Wyen C, Siehl J, Baumgarten A, Hensel M, Jessen A, Schaaf B, Vogel M, Bogner J, Horst HA, Stephan C (2013) HIV-associated lung cancer: survival in an unselected cohort. Scand J Infect Dis, 45(10):766-72 87. Hoffmann D, Mauroy A, Seebach J, Simon V, Wantia N, Protzer U (2013) New norovirus classified as a recombinant GII.g/GII.1 causes an extended foodborne outbreak at a university hospital in Munich. J Clin Virol, 58(1):24-30 88. Huang LR, Wohlleber D, Reisinger F, Jenne CN, Cheng RL, Abdullah Z, Schildberg FA, Odenthal M, Dienes HP, van Rooijen N, Schmitt E, Garbi N, Croft M, Kurts C, Kubes P, Protzer U, Heikenwalder M, Knolle PA (2013) Intrahepatic myeloid-cell aggregates enable local proliferation of CD8(+) T cells and successful immunotherapy against chronic viral liver infection. Nat Immunol, 14(6):574-583 89. Horwitz JA, Halper-Stromberg A, Mouquet H, Gitlin AD, Tretiakova A, Eisenreich TR, Malbec M, Gravemann S, Billerbeck E, Dorner M, Büning H, Schwartz O, Knops E, Kaiser R, Seaman MS, Wilson JM, Rice CM, Ploss A, Bjorkman PJ, Klein F, Nussenzweig MC (2013) HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice. Proc Natl Acad Sci USA, 110(41):16538-43 90. Huebner J, Rack-Hoch AL, Pecar A, Schmid I, Klein C, Borde JP (2013) Pilot project of a pediatric antibiotic stewardship initiative at the Hauner children‘s hospital. Klinische Pädiatrie, 225(4):223-9
101. Kayigire XA, Friedrich SO, Venter A, Dawson R, Gillespie SH, Boeree MJ, Heinrich N, Hoelscher M, Diacon AH (2013) Direct comparison of Xpert MTB/RIF with liquid and solid mycobacterial culture for the quantification of early bactericidal activity. J Clin Microbiol, 51(6):1894-8 102. Kirchner T, Hermann E, Möller S, Klinger M, Solbach W, Laskay T, Behnen M (2013) Flavonoides and 5-aminosalicylic acid inhibit the formation of neutrophil extracellular traps. Mediators Inflamm, 2013:710239
93. Jiménez-Soto LF, Clausen S, Sprenger A, Ertl C, Haas R (2013) Dynamics of the Cag-type IV secretion system of Helicobacter pylori as studied by bacterial co-infections. Cellular Microbiol, 15(11):19241937
103. Koehler RN, Alter G, Tovanabutra S, Saathoff E, Arroyo MA, Walsh AM, Sanders-Buell EE, Maboko L, Hoelscher M, Robb ML, Michael NL, McCutchan FE, Kim JH, Kijak GH (2013) Natural killer cell-mediated innate sieve effect on HIV-1: the impact of KIR/HLA polymorphism on HIV-1 subtype-specific acquisition in East Africa. J Infect Dis, 208(8):1250-4
94. Josten M, Reif M, Szekat C, Al-Sabti N, Roemer T, Sparbier K, Kostrzewa M, Rohde H, Sahl HG, Bierbaum G (2013) Analysis of the matrix-assisted laser desorption ionization-time of flight mass spectrum of Staphylococcus aureus identifies mutations that allow differentiation of the main clonal lineages. J Clin Microbiol, 51(6):1809-17
104. Kopp A, Gillespie TR, Hobelsberger D, Estrada A, Harper JM, Miller RA, Eckerle I, Müller MA, Podsiadlowski L, Leendertz FH, Drosten C, Junglen S (2013) Provenance and geographic spread of St. Louis encephalitis virus. Mbio, 4(3):e00322-13
95. Junglen S, Drosten C (2013) Virus discovery and recent insights into virus diversity in arthropods. Curr Opin Microbiol, 16(4):507-513
105. Koryakina I, McArthur J, Randall S, Draelos MM, Musiol EM, Muddiman DC, Weber T, Williams GJ (2013) Poly specific trans-acyltransferase machinery revealed via engineered acyl-CoA synthetases. ACS Chem Biol, 8(1):200-8
96. Kaebisch R, Mejías-Luque R, Prinz C, Gerhard M (2014) Helicobacter pylori cytotoxin-associated gene A impairs human dendritic cell maturation and function through IL-10-mediated activation of STAT3. J Immunol, 192(1):316-323 (epub 2013) 97. Kalsdorf B, Skolimowska KH, Scriba TJ, Dawson R, Dheda K, Wood K, Hofmeister J, Hanekom WA, Lange C, Wilkinson RJ (2013) Relationship between chemokine receptor expression, chemokine levels and HIV-1 replication in the lungs of persons exposed to Mycobacterium tuberculosis. Eur J Immunol, 43(2):540-549
106. Krämer B, Nischalke HD, Boesecke C, Ingiliz P, Voigt E, Mauss S, Stellbrink HJ, Baumgarten A, Rockstroh JK, Spengler U, Nattermann J (2013) Variation in IFNL4 genotype and response to interferon-based therapy of hepatitis C in HIV-positive patients with acute and chronic hepatitis C. AIDS, 27(17):2817-2819 107. Krebes J, Morgan RD, Bunk B, Spröer C, Luong K, Parusel R, Anton BP, König C, Josenhans C, Overmann J, Roberts RJ, Korlach J, Suerbaum S (2014) The complex methylome of the human gastric pathogen Helicobacter pylori. Nucleic Acids Res, 42(4):24152432 (Epub 2013)
98. Kang H*, Kreuels B*, Adjei O, Krumkamp R, May J, Small DS. *equally contributed (2013) The causal effect of malaria on stunting: a Mendelian randomization and matching approach. Int J Epidemiol, 42:1390-1398
108. Krüger A, Tannich E (2013) Rediscovery of Anopheles algeriensis Theob. (Diptera: Culicidae) in Germany after half a century. Eur Mosq Bulletin, 31:14-16
99. Kast K, Berens-Riha N, Zeynudin A, Abduselam N, Eshetu T, Löscher T, Andreas Wieser A, Shock J, Pritsch M (2013) Evaluation of Plasmodium falciparum gametocyte detection in different patient material. Malar J, 12:438
109. Krumkamp R, Sarpong N, Kreuels B, Ehlkes L, Loag W, Schwarz N, Zeeb H, Adu-Sarkodie Y, May J (2013) Health care utilization and symptom severity in Ghanaian children – a cross-sectional study. PLOS ONE, 8(11):e80598
100. Kawai K, Meydani SN, Urassa W, Wu D, Mugusi FM, Saathoff E, Bosch RJ, Villamor E, Spiegelman D, Fawzi WW (2014) Micronutrient supplementation and T cell-mediated immune responses in patients with tuberculosis in Tanzania. Epidemiol Infect, 142(7):1505-9 (Epub 2013)
110. Kuenne C, Billion A, Mraheil MA, Strittmatter A, Daniel R, Goesmann A, Barbuddhe S, Hain T, Chakraborty T (2013) Reassessment of the Listeria monocytogenes pan-genome reveals dynamic integration hotspots and mobile genetic elements as major components of the accessory genome. BMC Genomics, 14:47:00
Publications
82. Hellberg, L, Samavedam UK, Holdorf K, Hänsel M, Recke A, Beckmann T, Steinhorst K, Boehncke WH, Kirchner T, Möckel N, Solbach W, Zillikens D, Schmidt E, Ludwig RJ, Laskay T (2013) Methylprednisolone blocks autoantibody-induced tissue damage in experimental models of bullous pemphigoid and epidermolysis bullosa acquisita through inhibition of neutrophil activation. J Invest Dermatol, 133(10):2390-9
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111. Kurokawa K, Jung DJ, Ana JH, Fuchs K, Jeon YJ, Kim NH, Li X, Tateishi K, Park JA, Xia G, Matsushita M, Takahashi K, Park HJ, Peschel A, Lee BL (2013) Glycoepitopes of staphylococcal wall teichoic acid govern complement-mediated opsonophagocytosis via human serum antibody and mannose-binding letin. J Biol Chem, 288(43):30956-68
Publications
112. Kutscher S, Dembek CJ, Deckert S, Russo C, Körber N, Bogner JR, Geisler F, Umgelter A, Neuenhahn M, Albrecht J, Cosma A, Protzer U, Bauer T (2013) Overnight Resting of PBMC Changes Functional Signatures of Antigen Specific T- Cell Responses: Impact for Immune Monitoring within Clinical Trials. PLOS ONE, 8(10):e76215 113. Lanternier F, Pathan S, Vincent QB, Liu L, Cypowyj S, Prando C, Migaud M, Taibi L, AmmarKhodja A, Boudghene Stambouli O, Guellil B, Jacobs F, Goffard JC, Schepers K, del Marmol V, Boussofara L, Denguezli M, Larif M, Bachelez H, Michel L, Lefranc G, Hay R, Jouvion G, Chretien F, Fraitag S, Bougnoux ME, Boudia M, Abel L, Lortholary O, Casanova JL*, Picard C*, Grimbacher B*, Puel A*. *contributed equally and are considered aequo loco (2013) Deep dermatophytosis and inherited CARD9 deficiency. N Engl J Med, 369(18):1704-14 114. Lentz CS, Stumpfe D, Bajorat J, Famulok M, Hoerauf A, Pfarr KM (2013) New chemotypes for wALADin1-like inhibitorsof delta-aminolevulinic acid dehydratase from Wolbachia endobacteria. Bioorg MedChemLett, 23(20): 5558-5562 115. Leung CC, Lange C, Zhang Y (2013) Tuberculosis: current state of knowledge: an epilogue. Respirology, 18(7):1047-55 116. Liang F, Bond E, Sandgren KJ, Smed-Sörensen A, Rangaka MX, Lange C, Koup RA, McComsey GA, Lederman MM, Wilkinson RJ, Andersson J, Loré K (2013) Dendritic cell recruitment in response to skin antigen tests in HIV-1-infected individuals correlates with the level of T-cell infiltration. AIDS. 117. Lu I, Eberhard J, Ahmad F, Bhatnagar N, Behrens G, Jacobs R, Schmidt RE, Meyer-Olson D (2014) Elevated CD57 and CD95 expressions are associated with lower numbers of CD4⁺ recent thymic emigrants in HIV-1 infected immune responders following antiretroviral treatment. Immunol Lett, 158(1-2):1-6 (Epub 2013) 118. Lupberger J, Schaedler S, Peiran A, Hildt E (2013) Identification and characterization of a novel bipartite nuclear localization signal in the hepatitis B virus polymerase. World J Gastroenterol, 19(44):8000-10 119. Lutz P, Parcina M, Bekeredjian-Ding I, Hoerauf A, Strassburg CP, Spengler U (2014) Spontaneous bacterial peritonitis by Pasteurella multocida under treatment with rifaximin. Infection, 42(1):175-7 (Epub 2013)
120. Mann PA, Müller A, Xiao L, Pereira PM, Yang C, Lee SH, Wang H, Trzeciak J, Schneeweis J, Dos Santos MM, Murgolo N, She X, Gill C, Balibar CJ, Labroli M, Su J, Flattery A, Sherborne B, Maier R, Tan CM, Black T, Onder K, Kargman S, Monsma FJ, Pinho MG, Schneider T, Roemer T (2013) Murgocil is a Highly Bioactive Staphylococcal-specific Inhibitor of the Peptidoglycan Glycosyltransferase Enzyme MurG. ACS Chem Biol, 8(11):2442-51 121. Marklewitz M, Zirkel F, Rwego IB, Heidemann H, Trippner P, Kurth A, Kallies R, Briese T, Lipkin WI, Drosten C, Gillespie TR, Junglen S (2013) Discovery of a unique novel clade of mosquito-associated bunyaviruses. J Virol, 87(23):12850-65 122. Mast Y, Wohlleben W (2014) Streptogramins - Two are better than one! Int J Med Microbiol, 304:44-50 (Epub 2013) 123. Merker M, Kohl TA, Roetzer A, Truebe L, Richter E, Rüsch-Gerdes S, Fattorini L, Oggioni MR, Cox H, Varaine F, Niemann S (2013) Whole genome sequencing reveals complex evolution patterns of multidrug-resistant Mycobacterium tuberculosis Beijing strains in patients. PLOS ONE, 8(12):e82551 124. Mshana SE, Hain T, Domann E, Lyamuya EF, Chakraborty T, Imirzalioglu C (2013) Predominance of Klebsiella pneumoniae ST14 carrying CTX-M-15 causing neonatal sepsis in Tanzania. BMC Infect Dis, 13:466 125. Mullen L, Rigby A, Sclanders M, Adams G, Mittal G, Colston J, Fatah R, Subang C, Foster J, Francis-West P, Koster M, Hauser H, Layward L, Vessillier S, Annenkov A, Al-Izki S, Pryce G, Bolton C, Baker D, Gould D J, Chernajovsky Y (2013) Latency can be conferred to a variety of cytokines by fusion with latency-associated peptide from TGF-beta. Expert Opin Drug Deliv, 11(1):516 (Epub 2013) 126. Müller-Berghaus J, Volkers P, Scherer J, Cichutek K (2013) Besonderheit bei der Regulierung biologischer Arzneimittel in der individualisierten Medizin. Bundesgesundheitsbl – Gesundheitsforsch – Gesundheitsschutz , 56:1538-1544 127. Müller C, Dietz I, Tziotis D, Moritz F, Rupp J, Schmitt-Kopplin P (2013) Molecular cartography in acute Chlamydia pneumoniae infections – a non-targeted metabolomics approach. Anal Bioanal Chem, 405(15):5119-31 128. Mueller MC, Walentiny C, Seybold U, Nöstlinger C, Platteau T, Borms R, Draenert R, Bogner JR (2013) Sexual and reproductive health services for people living with HIV/AIDS in Germany: are we up to the challenge? Infection, 41:761-768
129. Musiol EM, Greule A, Härtner T, Wohlleben W, Weber T (2013) The AT2 Domain of KirCI Loads Malonyl Extender Units to the ACPs of the Kirromycin PKS. ChemBioChem, 14(11):1343-52 130. Nandakumar R, Nair S, Neumann B, Finsterbusch K, Grashoff M, Hochnadel I, Lienenklaus S, Wappler I, Steinmann E, Hauser H, Pietschmann T, Kröger A (2013) Hepatitis C Virus replication in mouse cells is restricted by IFN-dependent and IFN-independent mechanisms. Gastroenterology, 145(6):1414-23.e1 131. Nauerth M, Weissbrich B, Busch DH (2013) The clinical potential for koff-rate measurement in adoptive immunotherapy. Expert Reviews, 9(12):1151-3 132. Nauerth M, Weißbrich B, Knall R, Franz T, Dössinger G, Bet J, Paszkiewicz PJ, Pfeifer L, Bunse M, Uckert W, Holtappels R, Gillert-Marien D, Neuenhahn M, Krackhardt A, Reddehase MJ, Riddell SR, Busch DH (2013) TCR-ligand koff rate correlates with the protective capacity of antigen-specific CD8+ T cells for adoptive transfer. Science Translational Medicine, 5(192):192ra87 133. Neuenhahn M, Busch DH (2013) Whole-body anatomy of human T cells. Immunity, 38(1):10-2 134. Nkongolo S, Ni Y, Lempp FA, Kaufman C, Lindner T, Esser-Nobis K, Lohmann V, Mier W, Mehrle S, Urban S (2014) Cyclosporin A inhibits hepatitis B and hepatitis D virus entry by cyclophilin-independent interference with the NTCP receptor. J Hepatol, 60(4):723-731 (Epub 2013) 135. Overmann, J (2013) Principles of enrichment, isolation, cultivation, and preservation of bacteria. The Prokaryotes, 4th edition, Prokaryotic Biology and Symbiotic Associations. Springer, New York, pp 149-207 136. Pan KF, Formichella L, Zhang L, Zhang Y, Ma JL, Li ZX, Liu C, Wang YM, Goettner G, Ulm K, Classen M, You WC, Gerhard M (2013) Helicobacter pylori antibody responses and evolution of precancerous gastric lesions in a Chinese population. International Journal of Cancer, 134(9):2118-25 137. Pavlova S, Feederle R, Gärtner K, Fuchs W, Granzow H, Delecluse HJ (2013) An Epstein-Barr virus mutant produces immunogenic defective particles devoid of viral DNA. J Virol, 87(4):2011-22 138. Phillips PP, Bratton DJ, Nunn AJ, Hoelscher M (2013) Reply to Dodd and Proschan. J Infect Dis, 207(3):544-5 139. Ploen D, Hafirassou ML, Himmelsbach K, Schille SA, Biniossek ML, Baumert TF, Schuster C, Hildt E (2013) TIP47 is associated with the hepatitis C virus and its interaction with Rab9 is required for release of viral particles. Eur J Cell Biol, 92(12):374-82
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141. Rau SJ, Hildt E, Himmelsbach K, Thimme R, Wakita T, Blum HE, Fischer R (2013) CD40 inhibits replication of hepatitis C virus in primary human hepatocytes by c-Jun N terminal kinase activation independent from the interferon pathway. Hepatology, 57(1):23-36 142. Reiling N, Homolka S, Walter K, Brandenburg J, Niwinski L, Ernst M, Herzmann C, Lange C, Diel R, Ehlers S, Niemann S (2013) Clade-specific virulence patterns of Mycobacterium tuberculosis complex strains in human primary macrophages and aerogenically infected mice. MBio, 4(4):e00250-13 143. Reusken CB, Haagmans BL, Müller MA, Gutierrez C, Godeke GJ, Meyer B, Muth D, Raj VS, Smits-De Vries L, Corman VM, Drexler JF, Smits SL, El Tahir YE, De Sousa R, van Beek J, Nowotny N, van Maanen K, Hidalgo-Hermoso E, Bosch BJ, Rottier P, Osterhaus A, Gortázar-Schmidt C, Drosten C, Koopmans MP (2013) Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study. Lancet Infect Dis, 13(10):859-66 144. Rieger T, Merkler D, Günther S (2013) Infection of Type I Interferon Receptor-Deficient Mice with Various Old World Arenaviruses: A Model for Studying Virulence and Host Species Barriers. PLOS ONE, 8(8):e72290 145. Riess H, Clowes P, Kroidl I, Kowuor DO, Nsojo A, Mangu C, Schüle SA, Mansmann U, Geldmacher C, Mhina S, Maboko L, Hoelscher M, Saathoff E (2013) Hookworm infection and environmental factors in mbeya region, Tanzania: a cross-sectional, populationbased study. PLOS Negl Trop Dis, 7(9):e2408 146. Roemer T, Schneider T, Pinho MG (2013) Accessory Factors: A chink in the Armor of MRSA Resistance to β-lactam Antibiotics. Curr Opin Microbiol, 16(5):538-48 147. Roetzer A, Diel R, Kohl TA, Rückert C, Nübel U, Blom J, Wirth T, Jaenicke S, Schuback S, RüschGerdes S, Supply P, Kalinowski J, Niemann S (2013) Whole genome sequencing versus traditional genotyping for investigation of a Mycobacterium tuberculosis outbreak: a longitudinal molecular epidemiological study. PLOS Med, 10(2):e1001387 148. Roider J, Kalteis AL, Vollbrecht T, Gloning L, Stirner R, Henrich N, Bogner JR, Draenert R (2013) Adaptation of CD8 T cell responses to changing HIV-1 sequences in a cohort of HIV-1 infected individuals not selected for a certain HLA allele. PLOS ONE, 8(12):e80045
149. Rojas-Ponce G, Rachow A, Guerra H, Mapamba D, Joseph J, Mlundi R, Marimoto S, Ntinginya NE, Mangu C, Framhein A, Butler A, Kohlenberg A, Ngatemelela D, Froeschl G, Maboko L, Hoelscher M, Heinrich N (2013) A continuously monitored colorimetric method for detection of Mycobacterium tuberculosis complex in sputum. Int J Tuberc Lung Dis, 17(12):1607-12 150. Rolling T, Wichmann D, Schmiedel S, Burchard GD, Kluge S, Cramer JP (2013) Artesunate versus quinine in the treatment of severe imported malaria: comparative analysis of adverse events focussing on delayed haemolysis. Malar J, 12:241 151. Rotta Detto Loria J, Rohmann K, Droemann D, Kujath P, Rupp J, Goldmann T, Dalhoff K (2013) Nontypeable Haemophilus Influenzae Infection Upregulates the NLRP3 Inflammasome and Leads to Caspase-1-Dependent Secretion of Interleukin-1ß-A Possible Pathway of Exacerbations in COPD. PLOS ONE, 8(6):e66818 152. Rubbenstroth D, Ryll M, Knobloch JK, Köhler B, Rautenschlein S (2013) Evaluation of different diagnostic tools for the detection and identification of Riemerella anatipestifer. Avian Pathol, 42(1):17-26 153. Rückert C, Szczepanowski R, Albersmeier A, Goesmann A, Iftime D, Musiol EM, Blin K, Wohlleben W, Pühler A, Kalinowski J, Weber T (2013) Complete genome sequence of the kirromycin producer Streptomyces collinus Tü 365 consisting of a linear chromosome and two linear plasmids. J Biotechnol, 168:739-40 154. Rudolf M, Czajka C, Börstler J, Melaun C, Jöst H, von Thien H, Badusche M, Becker N, Schmidt-Chanasit J, Krüger A, Tannich E, Becker S (2013) First nationwide surveillance of Culex pipiens complex and Culex torrentium mosquitoes demonstrated the presence of Culex pipiens biotype pipiens / molestus hybrids in Germany. PLOS ONE, 8(9):e71832
158. Schmid H, Tokarska-Schlattner M, Füeßl B, Röder M, Kay L, Attia S, Lederer SR, Goebel FD, Schlattner U, Bogner JR (2013) Macro CK2 accumulation in tenofovir-treated HIV patients is facilitated by CK oligomer stabilization but is not predictive for pathology. Antivir Therapy, 18(2):193-204 159. Schmidt SK, Ebel S, Keil E, Woite C, Ernst JF, Benzin AE, Rupp J, Däubener W (2013) Regulation of IDO activity by oxygen supply: inhibitory effects on antimicrobial and immunoregulatory functions. PLOS ONE, 8(5):e63301 160. Schmitt C, Raggub L, Linnenweber-Held S, Adams O, Schwarz A, Heim A (2014) Donor origin of BKV replication after kidney transplantation. J Clin Virol, 59(2):120-125 (Epub 2013) 161. Schneider T, Müller A, Miess H, Gross H (2014) Cyclic lipopeptides as antibacterial agents - potent antibiotic activity mediated by intriguing mode of actions. Int J Med Microbiol, 304(1):3743 (Epub 2013) 162. Schommers P, Wyen C, Hentrich M, Gillor D, Zoufaly A, Jensen B, Bogner JR, Thoden J, Wasmuth JC, Fätkenheuer G, Hoffmann C (2013) Poor outcome of HIV-infected patients with plasmablastic lymphoma: results from the German AIDS-related lymphoma cohort study. AIDS, 27(5):842-5 163. Schorn M, Zettler J, Noel JP, Dorrestein P, Moore BS, Kaysser L (2014) The genetic basis for the biosynthesis of the pharmaceutically important class of epoxyketone proteasome inhibitors. ACS Chemical Biology, 9(1):301-309 (Epub 2013) 164. Schweikart J, May J (2013) Malaria – nur ein Problem der Tropen? Hyg Med, 38[9]: 366-371 165. Sethi S, Nanda R, Chakraborty T (2013) Clinical application of volatile organic compound analysis for detecting infectious diseases. Clin Microbiol Rev, 26(3):462-475
155. Sahner JH, Groh M, Negri M, Haupenthal J, Hartmann RW (2013) Novel small molecule inhibitors targeting the “switch region” of bacterial RNAP: Structure-based optimization of a virtual screening hit. Eur J Med Chem, 65,223-231
166. Shima K, Klinger M, Solbach W, Rupp J (2013) Activities of first-choice antimicrobials against gamma interferin-treated Chlamydia trachomatis differ in hypnoxia. Antimicrob Agents Chemother, 57(6):2828-30
156. Schäberle TF, Schiefer A, Schmitz A, König GM, Hoerauf A, Pfarr K (2014) Corallopyronin A – A promising antibiotic for treatment of filariasis. Int J Med Microbiol, 304(1):72-78 (Epub 2013)
167. Söhngen C, Bunk B, Podstawka A, Gleim D, Overmann J (2014) BacDive – The Bacterial Diversity Metadatabase. Nucl Acids Res, 42:D592D599 (Epub 2013)
157. Schiefer A, Vollmer J, Lämmer C, Specht S, Lenty C, Ruebsamen-Schaeff H, Brötz-Osterhelt H, Hoerauf A, Pfarr K (2013) The Wolbachia ClpP protease is a novel endobacterial target for antifilarial therapy. J Antimicrob Chemother, 68 (8): 1790-1800
168. Sola-Landa A, Rodríguez-García A, Amin R, Wohlleben W, Martín JF (2013) Competition between the GlnR and PhoP regulators for the glnA and amtB promoters in Streptomyces coelicolor. Nucleic Acids Res, 41:1767-82
Publications
140. Raj VS, Mou H, Smits SL, Dekkers DH, Müller MA, Dijkman R, Muth D, Demmers JA, Zaki A, Fouchier RA, Thiel V, Drosten C, Rottier PJ, Osterhaus AD, Bosch BJ, Haagmans BL (2013) Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature, 495(7440):251-4
56
169. Song F, Fux R, Provacia LB, Volz A, Eickmann M, Becker S, Osterhaus AD, Haagmans BL, Sutter G (2013) Middle East respiratory syndrome coronavirus spike protein delivered by modified vaccinia virus Ankara efficiently induces virus-neutralizing antibodies. J Virol, 87(21):11950-4
180. Tessema B, Beer J, Merker M, Emmrich F, Sack U, Rodloff AC, Niemann S (2013) Molecular epidemiology and transmission dynamics of Mycobacterium tuberculosis in Northwest Ethiopia: new phylogenetic lineages found in Northwest Ethiopia. BMC Infect Dis, 13:131
170. Specht S, Debrah AY, Klarmann U, Mand S, Hoerauf A, Pfarr K (2013) Chemotherapy of filariasis - established strategies and new developments. GMS Infect Dis, 1:1-10
181. Theilacker C, Held J, Allering L, Emmerich P, Schmidt-Chanasit J, Kern WV, Panning M (2013) Prolonged polyarthralgia in a German traveller with Mayaro virus infection without inflammatory correlates. BMC Infect Dis, 13(1):369
Publications
171. Spinner CD, Noe S, Schwerdtfeger C, Todorova A, Gaa J, Schmid RM, Busch DH, Neuenhahn M (2013) Acute hypophysitis and hypopituitarism in early syphilitic meningitis in a HIV-infected patient: a case report. BMC Infect Dis, 13:481 172. Sprinzl MF, Russo C, Kittner J, Allgayer S, Grambihler A, Bartsch B, Weinmann A, Galle PR, Schuchmann M, Protzer U, Bauer T (2013) Hepatitis B virus-specific T-cell responses during IFN administration in a small cohort of chronic hepatitis B patients under nucleos(t)ide analogue treatment. J Viral Hepatitis, doi: 10.1111/jvh.12189 173. Stauga S, Hahn A, Brattig NW, Fischer-Herr J, Baldus S, Burchard GD, Cramer JP (2013) Clinical relevance of different biomarkers in imported plasmodium falciparum malaria in adults: a case control study. Malar J, 12:246 174. Stecher B (2013) Finding a sugary foothold: how antibiotics pave the way for enteric pathogens. Cell Host Microbe, 14(3):225-227 175. Stecher B, Maier L, Hardt WD (2013) ‘Blooming‘ in the gut: how dysbiosis might contribute to pathogen evolution. Nat Rev Microbiol, 11(4):277-284 176. Sucipto H, Wenzel SC, Müller R (2013) Exploring chemical diversity of α-pyrone antibiotics: molecular basis of myxopyronin biosynthesis. ChemBioChem, 14(13):1581-1589 177. Suerbaum S (2013) The bugs within: interdisciplinary approaches to studying host-associated microbiota. FEMS Rev Microbiol, 37:633 178. Szaszak M, Shima K, Käding N, Hannus M, Solbach W, Rupp J (2013) Host metabolism promotes growth of Chlamydia pneumoniae ina low oxygen environment. Int J Med Microbiol, 303(5):239-46 179. Tan J, George S, Kusov Y, Perbandt M, Anemüller S, Mesters JR, Norder H, Coutard B, Lacroix C, Leyssen P, Neyts J, Hilgenfeld R (2013) 3C protease of enterovirus 68: Structurebased design of Michael acceptor inhibitors and their broad-spectrum antiviral effects against picornaviruses. J Virol, 87(8):4339-4351
182. Theron G, Zijenah L, Chanda D, Clowes P, Rachow A, Lesosky M, Bara W, Mungofa S, Pai M, Hoelscher M, Dowdy D, Pym A, Mwaba P, Mason P, Peter J, Dheda K; TB-NEAT team (2014) Feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing for tuberculosis in primarycare settings in Africa: a multicentre, randomised, controlled trial. Lancet, 383(9915):424-435 (Epub 2013) 183. Thoden J, Potthoff A, Bogner JR, Brockmeyer NH, Esser S, Grabmeier-Pfistershammer K, Haas B, Hahn K, Härter G, Hartmann M, Herzmann C, Hutterer J, Jordan AR, Lange C, Mauss S, Meyer-Olson D, Mosthaf F, Oette M, Reuter S, Rieger A, Rosenkranz T, Ruhnke M, Schaaf B, Schwarze S, Stellbrink HJ, Stocker H, Stoehr A, Stoll M, Träder C, Vogel M, Wagner D, Wyen C, Hoffmann C (2013) Therapy and prophylaxis of opportunistic infections in HIV-infected patients: a guideline by the German and Austrian AIDS societies (DAIG/ÖAG) (AWMF 055/066). Infection, 41 Suppl 2:S91-115 184. Tóth I, Le AQ, Hartjen P, Thomssen A, Matzat V, Lehmann C, Scheurich C, Beisel C, Busch P, Degen O, Lohse AW, Eiermann T, Fätkenheuer G, Meyer-Olson D, Bockhorn M, Hauber J, van Lunzen J, Schulze Zur Wiesch J (2013) Decreased frequency of CD73+CD8+ T cells of HIV-infected patients correlates with immune activation and T cell exhaustion. J Leukoc Biol, 94(4):551-61 185. Towhid ST, Schmidt EM, Tolios A, Münzer P, Schmidt E, Borst O, Gawaz M, Stegmann O, Lang F (2013) Stimulation of platelet death by vancomycin. Cell Physiol Biochem, 31:102-12 186. Towhid ST, Tolios A, Münzer P, Schmidt EM, Borst O, Gawaz M, Stegmann E, Lang F (2013) Stimulation of platelet apoptosis by balhimycin. Biochem Biophys Res Commun, 435:323-6 187. Tschan S, Brouwer AJ, Werkhoven PR, Jonker AM, Wagner L, Knittel S, Aminake MN, Pradel G, Joanny F, Liskamp RM, Mordmüller B (2013) Broad-spectrum antimalarial activity of peptido sulfonyl fluorides, a new class of proteasome inhibitors. Antimicrob Agents Chemother, 57(8):3576-3584
188. Vehreschild JJ (2013) Pneumonia and Lung Infiltrates in Neutropenic Patients: Many Stones Unturned. Ann Am Thorac Soc, 10(5):493-5 189. Vehreschild JJ, Morgen G, Cornely OA, Hartmann P, Koch S, Kalka-Moll W, Wyen C, Vehreschild MJ, Lehmann C, Gillor D, Seifert H, Kremer G, Fätkenheuer G, Jung N (2013) Evaluation of an infectious disease consultation programme in a German tertiary care hospital. Infection, 41(6):1121-8 190. Vehreschild M, Cornely OA (2013) Intestinal colonisation and blood stream infections due to vancomycin-resistant enterococci (VRE) and extendedspectrum beta-lactamase-producing Enterobacteriaceae (ESBLE) in patients with haematological and oncological malignancies. Infection, 41(5):1049-50 191. Vereide DT, Seto E, Chiu YF, Hayes M, Tagawa T, Grundhoff A, Hammerschmidt W, Sugden B (2013) Epstein-Barr virus maintains lymphomas via its miRNAs. Oncogene, 33(10):1258-1264 (Epub 2013) 192. Vollmer J, Schiefer A, Schneider T, Jülicher K, Johnston KL, Taylor MJ, Sahl HG, Hoerauf A, Pfarr K (2013) Requirement of lipid II biosynthesis for cell division in cell wall-less Wolbachia, endobacteria of arthropods and filarial nematodes. Int J Med Microbiol, 303: 140-149 193. Volz T, Allweiss L, M Barek MB, Warlich M, Lohse AW, Pollok JM, Alexandrov A, Urban S, Petersen J, Lütgehetmann M, Dandri M (2013) The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus. J Hepatol, 58:861-7 194. Vonberg RP, Höhle M, Aepfelbacher M, Bange FC, Belmar Campos C, Claussen K, Christner M, Cramer JP, Haller H, Hornef M, Fickenscher H, Fraedrich K, Knobloch JK, Kühbacher T, Manns MP, Nitschke M,Peter G, Pulz M, Rohde H, Roseland RT, Sayk F, Schaumburg F, Schöcklmann HO, Schubert S, Solbach W, Karch H, Suerbaum S (2013) Duraction of fecal shedding of Shiga toxisn-producing Escherichia coli o104:H4 in patients infected during the 2011 outbreak in Germany: a multicenter study. Clin Infect Dis, 56(8):1132-40 195. Wang R, Mast Y, Wang J, Zhang W, Zhao G, Wohlleben W, Lu Y, Jiang W (2013) Identification of two-component system AfsQ1/Q2 regulon and its cross-regulation with GlnR in Streptomyces coelicolor. Mol Microbiol, 87(1):30-48 196. Weidmann M, Frey S, Freire C, Essbauer S, Ruzek D, Klempa B, Zubrikova D, Vögerl M, Pfeffer M, Hufert FT, Zanotto PM, Dobler G (2013) Molecular phylogeography of tick-borne encephalitis virus in central Europe. J General Virology, 94:2129-2139
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198. Wiegand J, Wedemeyer H, Franke A, Rößler S, Zeuzem S, Teuber G, Wächtler M, Römmele U, Ruf B, Spengler U, Trautwein C, Bock CT, Fiedler GM, Thiery J, Manns MP, Brosteanu O, Tillmann HL, the German Hep-Net Acute Hepatitis B (GAHB) Study Group (2013) Treatment of severe, nonfulminant acute hepatitis B with lamivudine vs placebo: a prospective randomized double-blinded multicentre trial. J Viral Hepatitis, doi: 10.1111/jvh.12210 199. Wilmes M, Sahl HG (2014) Defensin-based anti-infective strategies. Int J Med Microbiol, 304(1):93-9 (Epub 2013 Sep 4) 200. Winstel V, Liang C, Sanchez-Carballo P, Steglic M, Munar M, Bröker BM, Penadés JR, Nübel U, Holst O, Dandekar T, Peschel A, Xia G (2013) Wall teichoic acid structure governs horizontal gene transfer between major bacterial pathogens. Nat Commun, 4:2345 8038 201. Winstel V, Xia G, Peschel A (2014) Pathways and roles of wall teichoic acid glycosylation in Staphylococcus aureus. Int J Med Microbiol, 304(34):215-21(Epub 2013) 202. Xia G, Wolz C (2014) Phages of Staphylococcus aureus and their impact on host evolution. Infect Genet Evol, 21:593-601 (Epub 2013) 203. Yang I, Nell S, Suerbaum S (2013) Surviving in hostile territory: The microbiota of the stomach. IFEMS Rev Microbiol, 37:736-761 204. Yang I, Eibach D, Kops F, Brenneke B, Woltemate S, Schulze J, Bleich A, Gruber AD, Muthupalani S, Fox JG, Josenhans C, Suerbaum S (2013) Intestinal microbiota composition of interleukin-10 deficient C57BL/6J mice and susceptibility to Helicobacter hepaticus-induced colitis. PLOS ONE, 8:e70783 205. Ye F, Zhang J, Liu H, Hilgenfeld R, Zhang R, Kong X, Li L, Lu J, Zhang X, Li D, Jiang H, Yang CG, Luo C (2013) Helix unfolding/refolding characterizes the functional dynamics of Staphylococcus aureus Clp protease. J Biol Chem, 288(24):17643-53 206. Zhou P, Chen Z, Yan Q, Yang S, Hilgenfeld R, Jiang Z (2013) The structure of a glycoside hydrolase family 81 endo-ß-1,3-glicanase. Acta Crystallogr D Biol Crystallogr, 69(Pt 10):2027-38 207. Ziegler U, Angenvoort J, Klaus C, Nagel-Kohl U, Sauerwald C, Thalheim S, Horner S, Braun B, Kenklies S, Tyczka J, Keller M, Groschup MH (2013) Use of competition ELISA for monitoring of West Nile virus infections in horses in Germany. Int J Environ Res Public Health, 10(8):3112-20
208. Zielecki F, Weber M, Eickmann M, Spiegelberg L, Zaki AM, Matrosovich M, Becker S, Weber F (2013) Human cell tropism and innate immune system interactions of human respiratory coronavirus EMC compared to those of severe acute respiratory syndrome coronavirus. J Virol, 87(9):5300-4 209. Zirkel F, Roth H, Kurth A, Drosten C, Ziebuhr J, Junglen S (2013) Identification and characterization of genetically divergent members of the newly established family Mesoniviridae. J Virol, 87(11):6346-58 210. Zoufaly A, Cramer JP, Vettorazzi E, Sayk F, Bremer JP, Koop I, de Weerth A, Schmiedel S, Jordan S, Fraedrich K, Asselborn NH, Nitschke M, Neumann-Grutzeck C, Magnus T, Rüther C, Fellermann K, Stahl RK, Wegscheider K, Lohse AW (2013) Risk factors for development of hemolytic uremic syndrome in a cohort of adult patients with STEC 0104:H4 infection. PLOS ONE, 8(3):e59209
Publications
197. Weissbrich B, Nauerth M, Busch DH (2013) Adoptive immunotherapy: New assay for the identification of T cells with optimal avidity. Landes Bioscience, 2(10):e26199
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Project coordination: DZIF Press Office Realisation and text : scienceRELATIONS Hannover/Berlin Layout: www.spezial-kommunikation.de Photos: DZIF/scienceRELATIONS except: p. 10, 11 (Institute for Tropical Medicine, University Hospital Tübingen), p. 33 (Martin Joppen)
German Center for Infection Research (DZIF e.V.) Main Office Inhoffenstraße 7 | D-38124 Braunschweig T +49 (0)531-61 81-11 52 F +49 (0)531-61 81-11 53
[email protected] | www.dzif.de
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