The molecular pathogenesis of Y. pestis in relevant animal models has been relatively neglected because of the scarcity of secure BSL-3 facilities and trained personnel. The threat of bioterrorism and the emergence of multiply-antibiotic resistant strains of Y. pestis increases the urgency for a more detailed understanding of the host-pathogen relationship at the molecular level that may lead to the design of improved medical countermeasures and diagnostics. RML is one of the few sites in the world where plague pathogenesis can be comprehensively studied at the molecular level. The objective of this project is to establish mouse and rat models of bubonic plague that incorporate flea-to-rodent transmission to investigate the role of specific Y. pestis virulence factors and to characterize the host response to naturally acquired infection. We have established a rat model of bubonic plague and characterized the kinetics, microbiology, and histopathology of bubonic plague in rats following intradermal injection of Y. pestis. We used this model to characterize the gene expression profile of Yersinia pestis in the infected lymph node during bubonic plague, using whole-genome microarray technology. Based on these results, we tested the virulence of specific Y. pestis mutant strains to determine the role of bacterial genes predicted to be important in resistance to the host innate immune response. During the past year we have characterized the rat gene expression response to early infection in the lymph node during bubonic plague. We have developed models to examine host-parasite interactions in the dermis after transmission by flea bite and the effects of flea saliva on this interaction. We determined that the Y. pestis Nha membrane sodium antiporter is required for virulence in mice. In collaboration with Susan Buchanan (NIDDK) we demonstrated that immunoreactivity to the Y. pestis outer surface Ail protein is characteristic of a protective immune response to plague, and are evaluating this protein as a candidate diagnostic antigen and vaccine component.
