Chapter 17 Yersinia pestis
17.1 General overview of Yersinia pestis and plague
Yersinia pestis, the causative agent of plague, is a Gram-negative facultative anaerobic bipolarstaining bacillus bacterium belonging to the family Enterobacteriaceae. It has been classified as a Category A bioterrorism agent for public health preparedness by U.S. Centers for Disease Control and Prevention. Plague is a dreadful disease of long standing. It has been the cause of three pandemics, and has led to the deaths of millions of people, the devastation of cities and villages, and the collapse of governments and civilizations. Small outbreaks of plague continue to occur throughout the world, and at least 2000 cases of plague are reported annually. At the present time, plague remains a serious problem for international public health, and its risk has been assessed using quantitative modeling approaches.Plague may be manifested in one of three forms: bubonic, pneumonic and septicemic (Lathem et al. 2005). Among the three forms of plague, pneumonic plague is particularly dangerous, with incubation period of 3 to 5 days and mortality rate approaching 100% unless antibiotic treatment is initiated within 24 hours of the onset of symptoms. Plague is transmitted to humans from infected flees and rodents are reservoirs of the disease. While over 200 mammalian species have been reported to be naturally infected with Y. pestis, rodents are the most important hosts for plague (Perry and Fetherston 1997). Currently, most human plague cases in the world are classified as sylvatic plague, namely infection from rural wild animals such as mice, chipmunks, squirrels, gerbils, marmots, voles and rabbits (Christie 1982).Transmission between rodents is achieved by their associated fleas from the infected blood of the host. The organism is not transovarially transmitted from flea-to-flea, and artificially infected larvae clear the organism within 24 hours. Therefore, maintenance of plague in environment is dependent upon cyclic transmission between fleas and mammals (Perry and Fetherston 1997).
17.2 Summary Data Lathem et al. (2005) and Parent et al. (2005) respectively inoculated C57BL/6 mice intranasally
with the Y. pestis virulent wild-type CO92 strain and with the KIM D27 strain. Rogers et al. (2007) administered the Y. pestis CO92 strain to BALB/c mice via intraperitoneal route. Table 17.1. Summary of the Y. pestis data and best fits
Experiment Number
Reference
Host Type/Pathogen Strain
Route/ # of Doses
Dose Units
Response
Best Fit Model
Optimized Parameter(s)
LD50
1
Lathem et al, 2005
Mouse/ CO92
Intranasal/4
CFU
death
Exponential
K=1.63E-3
426.08
2
Parent et al, 2005
Mouse/ KIM D27
Intranasal/4
CFU
death
Exponential
K=1.07E-4
6473
3
Rogers et al, 2007
Mouse/ CO92
Intraperitoneal/5
CFU
death
Exponential
K=3.45E-2
20.12
17.3 Optimized Models and Uncertainty and Fitting Analyses 17.3.1. Output for experiment 1. Table 17.2: Mouse/ CO92 model data Dose Dead Survived Total 1.00E+02 1 3 4 1.00E+03 3 1 4 1.00E+04 4 0 4 1.00E+05 4 0 4 Lathem et al, 2005.
Table 17.3. Goodness of Fit and Model Selection χ20.95,1 Model
Deviance
Exponenti al
0.34
∆
DF
0.14
2
p-value 7.81
3 0.20
Beta Poisson
pvalue
χ20.95,m-k
3.84 0.659
0.953 5.99 0.931
Exponential is best fitting model
Table 17.4 Optimized parameters for the best fitting (exponential), obtained from 10,000 bootstrap iterations Parameter
MLE Estimate
Percentiles 0.5%
2.5%
5%
95%
97.5%
99.5%
k
0.0016
3.62E-04
5.5E-04
6.22E-04
7.02E-03
7.02E-03
1.39E-02
LD50 (spores)
426.08
45.00
98.71
98.71
1114.95
1261.23
1916.64
Figure 17.1 Parameter histogram for exponential model (uncertainty of the parameter)
Figure 17.2 Exponential model plot, with confidence bounds around optimized model
17.3.2. Output for experiment 2. Table 17.5: Mouse/ KIM D27 model data Dose Dead Survived Total 1.00E+02 0 10 10 1.00E+03 2 8 10 1.00E+04 6 4 10 1.00E+05 10 0 10 Parent et al, 2005.
Table 17.6. Goodness of Fit and Model Selection χ20.95,1 Model
Deviance
Exponenti al
1.21
∆
DF
3 0.14
Beta Poisson
1.07
2
pvalue
χ20.95,m-k p-value 7.81
3.84
0.750
0.711
5.99 0.585
Exponential is best fitting model Table 17.7 Optimized parameters for the best fitting (exponential), obtained from 10,000 bootstrap iterations Parameter
MLE Estimate
Percentiles 0.5%
2.5%
5%
95%
97.5%
99.5%
k
1.07E-04
3.85E-05
4.89E-05
5.57E-05
1.93E-04
2.22E-04
3.29E-04
LD50 (spores)
6473
2106
3121
3593
12446
14175
18025
Figure 17.3 Parameter histogram for exponential model (uncertainty of the parameter)
Figure 17.4 Exponential model plot, with confidence bounds around optimized model
17.3.3. Output for experiment 3. Table 17.8: Mouse/ CO92 model data Dose Dead Survived Total 2.00E+00 0 20 20 8.00E+00 5 15 20 2.60E+01 13 7 20 7.40E+01 9 1 10 2.57E+02 10 0 10 Rogers et al, 2007.
Table 17.9. Goodness of Fit and Model Selection χ20.95,1 Model
Deviance
Exponenti al
3.12
Beta Poisson
3.12
∆
DF
4 1.00 E-04 3
pvalue
χ20.95,m-k p-value 9.49
3.84
0.539
0.992
7.81 0.374
Exponential is best fitting model
Table 17.10 Optimized parameters for the best fitting (exponential), obtained from 10,000 bootstrap iterations Parameter
MLE Estimate
Percentiles 0.5%
2.5%
5%
95%
97.5%
99.5%
k
0.034
0.020
0.023
0.024
0.049
0.053
0.061
LD50 (spores)
20.12
11.44
13.03
14.11
28.43
30.26
34.77
Figure 17.5 Parameter histogram for exponential model (uncertainty of the parameter)
Figure 17.6 Exponential model plot, with confidence bounds around optimized model
17.4. Summary Noting a significant difference of LD50 between the inhalation (1.4x104 pfu) and subcutaneous (0.2 pfu) routes has been identified, which suggests a substantial variation of virulence with infection site. This could also attribute to the difference between out-bred and in-bred origins.
References Christie, A. B. (1982). "Plague: review of ecology." Ecol. Dis. 1: 111-115. Lathem, W. W., et al. (2005). "Progression of Primary Pneumonic Plague: A Mouse Model of Infection, Pathology, and Bacterial Transcriptional Activity." Proceedings of the National Academy of Sciences of the United States of America 102(49): 17786-17791. Parent, M. A., et al. (2005). "Cell-Mediated Protection against Pulmonary Yersinia pestis Infection." Infection and Immunity 73(11): 7304-7310. Perry, R. D. and J. D. Fetherston (1997). "Yersinia pestis-Etiologic Agent of Plague." Clinical Microbiology Reviews 10(1): 35-66. Rogers, J. V., et al. (2007). "Transcriptional Responses in Spleens from Mice Exposed to Yersinia pestis CO92." Microbial Pathogenesis 43: 67-77.
