Yersinia Pestis Modulation of Host Extracellular Vesicles

Abstract Extracellular vesicles (EVs) facilitate intercellular communication by the delivery of protein, lipid, and small RNAs that mediate changes in recipient cells. Importantly, the cargo packaged within EVs rapidly changes in response to physiological changes in the EV producing cells, allowing cells to communicate local changes in physiology, including infection. Recently, we discovered that Yersinia pestis actively inhibits the biogenesis and release of EVs by human neutrophils through the cooperative action of three proteins that the bacteria directly translocate into neutrophils via a type three secretion system. Moreover, we demonstrated that these alterations in EV biogenesis by Y. pestis inhibit the antimicrobial and inflammatory capacity of neutrophil- derived EVs. Because EVs are vital for intercellular communication between immune cells, we hypothesize that the alteration of the EV biogenesis by Y. pestis significantly contributes to the ability of the bacteria to dysregulate inflammation and establish infection. Our primary goals in this grant are to (1) define changes in pulmonary EV populations and inflammatory potential during pneumonic plague, and (2) use Y. pestis mutants to delineate the molecular mechanisms of EV biogenesis in neutrophils. The completion of these aims will not only improve our understanding of Y. pestis virulence and immune evasion but will significantly expand our comprehension of the molecular mechanisms responsible for EV biogenesis by neutrophils and the role of EVs in the regulation of inflammation during acute bacterial infections.