Defining the impact of Extracellular Vesicles on inflammation during pneumonic plague

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PROJECT SUMMARY/ABSTRACT During infection, immune cells rely on communication to productively target and eliminate invading pathogens. Extracellular vesicles (EVs) are one key mediator of intercellular communication between immune cells. These membrane-bound vesicles contain proteins, lipids, and nucleic acids that represent the inflammatory state of a given cell. Upon release, these EVs can fuse with other immune cells, establishing biochemical communication between cells and amplifying the inflammatory response to augment pathogen clearance. Yersinia pestis is the etiologic agent of the human disease known as plague. A hallmark of this disease is the sophisticated suppression of the host immune system in a biphasic manner. During acute infection, Y. pestis utilizes its type 3 secretion system (T3SS) to inject effector proteins into host cells which disrupt signaling pathways essential for bacterial clearance. Thus, acute infection is hallmarked by the maintenance of a non-inflammatory environment in which the bacteria can proliferate without host intervention. The second stage of infection, the pro- inflammatory phase, begins 36-48 hours post-infection, in which the host begins to successfully mount an immune response against the pathogen. However, the bacterial load ultimately overwhelms the host delayed responses, at which point the host may succumb to infection. Previous work has demonstrated that the generation of this non-inflammatory environment during acute infection is essential for Y. pestis virulence. While numerous studies have highlighted the importance of suppressing phagocytosis, exocytosis, and other antibacterial responses, there is a gap in knowledge of how Y. pestis manipulates the EV response and how this impacts intercellular communication. Preliminary studies suggest that Y. pestis can manipulate the proteins packaged into EVs by neutrophils in vitro. These data support the hypothesis that Y. pestis disrupts EVs production during infection to alter inflammation. The studies presented here will expand on our preliminary data by delineating the in vivo EV response during pneumonic plague (Aim 1) and defining the impact of EVs on immune modulation (Aim 2). These studies will be the first to investigate the role of EV-mediated intracellular communication during plague. Therefore, completion of these aims will significantly improve our understanding of how. Y. pestis exploits EV trafficking to manipulate the host immune response.