Factors Affecting Dissemination Events Early in Bubonic Plague

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DESCRIPTION (provided by applicant): Yersinia pestis is the causative agent of disease in a variety of mammals, and humans can become infected when human and animal ecologies intersect. This has led to several pandemics of plague in human history, and infection with Y. pestis is currently considered by the WHO as a re-emerging infectious disease because of the increased incidence in a wide number of countries. Bubonic plague is the most common form of disease and the untreated mortality rate is estimated at 40-70%. A number of recent studies from several groups suggest that Y. pestis actively causes immunosuppression early during infection. Furthermore, recent studies have shown that very early events after inoculation are responsible for determining the outcome of infection. One of the first steps in the pathogenesis of bubonic plague is dissemination of the pathogen from the inoculation site (IS) to the draining lymph node (DLN). It has long been believed that the bacteria disseminate to the DLN by trafficking in phagocytic cells. However, there is strikingly little in vivo data demonstrating this. We hypothesize that Y. pestis actively influences these early dissemination events by interacting with key components of the host innate response. Our long-term goal is to understand the mechanism of dissemination of Y. pestis from the IS to the DLN. Using an intradermal route (the route that most closely mimics that of the flea) of inoculation and a dissemination assay we recently developed, we are able to monitor the transit of bacteria to the DLN from the IS, and subsequently to systemic tissues. Here, we will specifically test in vivo (a) the widely held belief that phagocytic cells are important for traffiking Y. pestis from the IS to the DLN, and (b) effects by the Y. pestis virulence factors known to affect interactions with phagocytic cells in vitro for their impact on early dissemination to the DLN.