Early Events in the Pathogenesis of Pneumonic Plague

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DESCRIPTION (provided by applicant): Pneumonic plague is the deadliest form of disease caused by Yersinia pestis and the basis for this bacterium's classification as a Category A Select Agent. Most studies of plague pathogenesis have focused on the bubonic route of infection, and most research on the pathogen has been performed with attenuated, avirulent or related species of Yersinia. A more complete picture of pneumonic plague has emerged from the development of a mouse model of infection showing that pulmonary disease caused by fully virulent Y. pestis progresses in two distinct stages: an extended pre-inflammatory phase followed by a robust pro-inflammatory phase that leads to severe bronchopneumonia and mortality. The ultimate goal of this proposal is to obtain a more complete understanding of respiratory immune cell interactions, activation and depletion by Y. pestis during the pre-inflammatory phase of pneumonic plague. We will use both bacterial and host mutants to further characterize the effects of these early bacterial - host cell interactions on pathogenesis. Specific Aim 1. Characterize early interactions between Y. pestis and host cells in the lung. Our hypothesis is that Y. pestis targets specific immune cell populations in the lung to achieve directed and localized suppression of innate immunity. The studies in this Aim will characterize the lung cells targeted by the type III secretion system in vivo and evaluate host cell population changes that occur during the preinflammatory phase. Specific Aim 2. Characterize Y. pestis-mediated inflammasome activation and its contribution to disease progression/pathology. Preliminary data demonstrates that fully virulent Y. pestis activates the inflammasome soon after inoculation both in vitro and in vivo. This is striking, as no signs of inflammation or pathology are visible at this early stage of infection. The studies in this Aim are designed to identify both the bacterial and host contributor to this response, as well as evaluate the importance of this early cytokine activation to later immunopathogenesis.