The molecular pathogenesis of fully virulent, wild-type Y. pestis in relevant animal models has been relatively neglected because of the scarcity of secure BSL-3 facilities and trained personnel certified to work with this Class A select agent. 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. We have established 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 characterized the kinetics, microbiology, and histopathology of bubonic plague in rats following intradermal injection of Y. pestis, and 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. This year, for example, in collaboration with extramural investigators we characterized two new Y. pestis virulence factors (bibliography references 2 and 4). Our previous work has shown that three important Y. pestis virulence factors, Ail (a Y. pestis outer surface protein), the Type III secretion system (T3SS) encoded on the Yersinia virulence plasmid, and the plasminogen activator (Pla) encoded on the 9.5-kb Y. pestis-specific plasmid all act to limit the polymorphonuclear leukocyte response to bubonic plague infection in vivo (polymorphonuclear leukocytes, also referred to as PMNs or neutrophils, are phagocytic cells that are an important innate defense against infection). Thus, we now have several lines of evidence that the PMN response correlates with successful outcome to infection, and this aspect of host-pathogen interaction has become a focus of our lab. During the past year, we characterized the cellular innate immune response to deposition of Y. pestis in the dermis (cf. bibliography references 1 and 5), using the mouse ear model and intravital imaging systems developed in previous years. An important finding is that Y. pestis is able to suppress the activation of PMNs that are recruited to the site of infection. We also reported (bibliography reference 3) that the Y. pestis insecticidal-like toxins that are highly produced during infection of the flea do not have any discernible biological role in the flea, but instead may be important for subverting the innate immune response immediately following transmission due to their ability to inhibit phagocytosis by PMNs and macrophages. We are conducting trials to determine the efficacy of the Ail protein as a component of a third-generation anti-plague vaccine. In addition to Ail, we are studying other Y. pestis factors that counteract PMN function, including the T3SS and the Y. pestis insecticidal-like toxins that are upregulated in the flea. In summary, we have established relevant animal models and are using them to comprehensively study the infection biology of bubonic plague.

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Spinner, Justin L; Hasenkrug, Aaron M; Shannon, Jeffrey G et al. (2016) Role of the Yersinia YopJ protein in suppressing interleukin-8 secretion by human polymorphonuclear leukocytes. Microbes Infect 18:21-9
Shannon, Jeffrey G; Bosio, Christopher F; Hinnebusch, B Joseph (2015) Dermal neutrophil, macrophage and dendritic cell responses to Yersinia pestis transmitted by fleas. PLoS Pathog 11:e1004734
Spinner, Justin L; Winfree, Seth; Starr, Tregei et al. (2014) Yersinia pestis survival and replication within human neutrophil phagosomes and uptake of infected neutrophils by macrophages. J Leukoc Biol 95:389-98
Spinner, Justin L; Carmody, Aaron B; Jarrett, Clayton O et al. (2013) Role of Yersinia pestis toxin complex (Tc) family proteins in resistance to phagocytosis by polymorphonuclear leukocytes. Infect Immun :
Minato, Yusuke; Ghosh, Amit; Faulkner, Wyatt J et al. (2013) Na+/H+ antiport is essential for Yersinia pestis virulence. Infect Immun 81:3163-72
Lukacik, Petra; Barnard, Travis J; Hinnebusch, B Joseph et al. (2013) Specific targeting and killing of Gram-negative pathogens with an engineered phage lytic enzyme. Virulence 4:90-1
Seo, Keun Seok; Kim, Jong Wan; Park, Joo Youn et al. (2012) Role of a new intimin/invasin-like protein in Yersinia pestis virulence. Infect Immun 80:3559-69
Bosio, Christopher F; Jarrett, Clayton O; Gardner, Donald et al. (2012) Kinetics of innate immune response to Yersinia pestis after intradermal infection in a mouse model. Infect Immun 80:4034-45
Spinner, Justin L; Hinnebusch, B Joseph (2012) The life stage of Yersinia pestis in the flea vector confers increased resistance to phagocytosis and killing by murine polymorphonuclear leukocytes. Adv Exp Med Biol 954:159-63
Lukacik, Petra; Barnard, Travis J; Keller, Paul W et al. (2012) Structural engineering of a phage lysin that targets gram-negative pathogens. Proc Natl Acad Sci U S A 109:9857-62

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