Chapter 4 Coxiella burnetii

Transcription

1 Chapter 4 Coxiella burnetii 4. General overview of Coxiella burnetii and Q fever Coxiella burnetii (C. burnetii), an obligate intracellular gram-negative bacterium, is the causative agent of Q fever. C. burnetii multiplies only within the phagolysosomal vacuoles, particularly the macrophages of the host. During natural infections, the organism grows to high numbers in placental tissues of animals such as goats, sheep, and cows. The Center for Disease Control and Prevention (CDC) has classified C. burnetii as a category B biological terrorist agent because it consistently causes disability, can be manufactured on a large scale, remains stable under production, storage, and transportation conditions, can be efficiently disseminated and remains viable for years after dissemination. Q fever, a zoonotic disease found worldwide, may manifest as acute or chronic disease. The acute form is generally not fatal and manifests as self-controlled febrile illness. Chronic Q fever is usually characterized by endocarditis. Many animal models, including humans, have been studied for Q fever infection through various exposure routes. Humans are infected primarily through inhalation of aerosolized C. burnetii with as few as 0 organisms causing disease. Aerosols, or airborne particles, easily cause infection even without contact with infected animals, whereas person-to-person infection is rare. Ingestion of contaminated dairy products or bites from infected ticks may also lead to infection but these modes of transmission are very rare. However, there have been some recorded cases of human Q fever caused by the consumption of unpasteurized goat milk products (Tamrakar et al. 20). 4.2 Summary Data Williams and Cantrell (982) interperitoneally inoculated groups of C57BL/0ScN male mice with different doses of C. burnetii phase I Ohio strain to develop a vaccine against Q fever. Scott and Williams (987) examined the susceptibility of inbred mice to infection by C. burnetii Nine mile phase I strain. As many as 47 strains of inbred mice were evaluated. Groups of resistant C57BL/6J mice were inoculated with mean doses ranging from 0.3 to 0 7 organisms. The mortalities at various doses were recorded. 22

2 Table 4.. Summary of the Coxiella burnetii data and best fits Experiment number 2 Reference Williams et al., 982 Scott et al., 987 Host type/patho gen strain mice/ phase I Ohio strain mice/ Nine mile phase I strain Route / number of doses interperito neal/0 interperito neal/3 Dose unit No. of organis ms No. of organis ms Response death The data from different experiments were not able to be statistically pooled. Best-fit model Beta- Best-fit parameters α = 0.36 N 50 = 4.93E E+08 death Exponential K=5.70E-.22E+0 23

3 4.3 Optimized Models and Fitting Analyses 4.3. Optimization Output for experiment Table 4.2. Mice/ phase I Ohio strain model data Dose Dead Survived Total 7.00E E E E E E E E E E Williams et al., 982. Table 4.3. Goodness of Fit and Model Selection Model Deviance DF Exponent ial Beta Beta is best fitting model χ , p- value χ ,m-k p-value Table 4.4 Optimized parameters for the best fitting (beta ), obtained from 0,000 bootstrap iterations Parameter MLE Estimate Percentiles 0.5% 2.5% 5% 95% 97.5% 99.5% α N E (spores) 4.93E+08.9E E E E+08.08E+09.39E+09 Figure 4. Parameter scatter plot for beta model ellipses signify the 0.9, 0.95 and 0.99 confidence of the parameters. Figure 4.2 beta model plot, with confidence bounds around optimized model 24

4 4.3 Optimized Models and Fitting Analyses Optimization Output for experiment 2 Table 4.5 Mice/ Nine mile phase I strain model data Dose Dead Survived Total 5.0E E E E E E E E E E E E E Scott et al., 987. Table 4.6. Goodness of Fit and Model Selection Model Deviance DF Exponenti al Beta Exponential is best fitting model χ , p- value χ ,m-k p-value Table 4.7 Optimized parameters for the best fitting (exponential), obtained from 0,000 bootstrap iterations Parameter MLE Estimate Percentiles 0.5% 2.5% 5% 95% 97.5% 99.5% k 5.70E- 2.30E- 2.94E- 3.3E-.38E-0.56E-0 2.3E-0 (spores).22e E E E E E E+0 Figure 4.3 Parameter histogram for exponential model (uncertainty of the parameter) Figure 4.4 Exponential model plot, with confidence bounds around optimized model 25

5 4.4. Summary Noting an apparent difference of between the experiment (4.93x0 8 ) and experiment 2 (.22 x0 0 ) routes has been identified. This may reflect the difference of susceptibilities associated with different host and pathogen strains. References Scott, G. and J. C. Williams (987). "Pathological responses of inbred mice to phase I Coxiella Burnetii." Journal of General Microbiology 33(3): Tamrakar, S. B., A. Haluska, C. N. Haas and T. A. Bartrand (20). "Dose-Response Model of Coxiella burnetii (Q Fever)." Risk Analysis 3(): Williams, J. C. and J. L. Cantrell (982). "Biological and immunological properties of Coxiella burnetii vaccines in C57BL/OScN endotoxin-nonresponder mice." Infection and Immunity 35(3):