Elucidating the Biogenesis of the Yersinia pestis Containing Vacuole

University Of Louisville, Louisville KY

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Abstract

? DESCRIPTION (provided by applicant): Yersinia pestis is a facultative intracellular pathogen that causes the disease known as plague. Growing evidence indicates that intracellular growth in macrophages is important for Y. pestis virulence. Upon phagocytosis, Y. pestis alters the maturation of the phagosome to generate a protective compartment within the cell known as the Yersinia containing vacuole (YCV). Key steps in the generation of the YCV include inhibition of YCV acidification, expansion into a spacious vacuole, and acquisition of the autophagic markers. However, the mechanisms used by the bacterium to subvert the normal phagosome maturation process and generate the YCV have not been defined. Recently we have identified a subset of host Rab GTPases that are required for Y. pestis to survive within macrophages. Because Rab proteins are key mediators of vesicular trafficking, phagosome maturation, and autophagy, we hypothesize that these GTPases are required by Y. pestis to subvert phagosome maturation and generate the YCV, thus protecting the bacterium from macrophage clearance. As Rab proteins mediate many aspects of vesicular trafficking through direct interactions with specific organelles and recruitment of effector proteins, in Aim 1 we will determine if Rab GTPase required for Y. pestis intracellular survival are specifically recruited to the YCV. In Aim 2, we will determine the contribution of individual Rab proteins on the biogenesis of the YCV. These studies will be the first to define the contribution of host Rab GTPases to the formation of the YCV. Ultimately, understanding the YCV biogenesis process will enable us to identify Y. pestis pathogenicity factors that contribute to intracellular survival.