This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Yersinia pestis, the causative agent of plague, is one of the most virulent and notorious of all human pathogens. Plague is characterized by the rapid progression of fulminant disease and an extremely high morbidity and mortality rate. Initiation of Y. pestis infection results in a rapid innate immune response including recruitment of polymorphonuclear leukocytes (PMNs or neutrophils). Progression of disease is accompanied by systemic neutrophilia and pronounced increase of extracellular Y. pestis. The ability of PMNs to phagocytose and kill bacterial pathogens is essential for maintenance of human health. Although the majority of microorganisms are readily killed by neutrophils, several bacterial pathogens have evolved the capability to subvert the human innate immune system to cause disease. Strategies used by bacteria to circumvent innate host defense are extremely diverse and include evasion of phagocytosis, resistance to killing, and induction of apoptosis. Unfortunately, there are few studies that specifically address the role of human PMNs in the innate immune response to Y. pestis. We recently demonstrated that Y. pestis obtained from infected fleas develop resistance to killing by human PMNs. In addition, we have strong preliminary data that suggest that Y. pestis is capable of modulating factors that contribute to increased resistance to phagocytosis by human PMNs and rapidly promoting apoptosis. These findings lead to the overarching hypothesis that Y. pestis circumvents neutrophil killing to cause disease.
Three specific aims have been developed to test the specific hypothesis that Y. pestis produces factors that modulate essential PMN processes such as bactericidal activity and apoptosis.
Specific aims i nclude: (1) characterizing the role of known Y. pestis virulence factors on PMN function, (2) to elucidate Y. pestis mechanisms for triggering apoptosis in human PMNs, and (3) to investigate Y. pestis genes involved in the interaction with human PMNs. The data generated from these specific aims will greatly enhance our understanding of the role of immune evasion in the pathogenesis of plague.
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