Yersinia pestis is a facultative intracellular pathogen that causes the human 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. Our long term goals are to elucidate the mechanisms by which Y. pestis evades macrophage killing and define the contribution of intracellular survival to Y. pestis virulence. Recently we discovered that Y. pestis manipulates the host endocytic recycling pathway to survive in macrophages. Moreover, we have demonstrated that Y. pestis recruits Rab1, Rab4 and Rab11 to the YCV. Importantly, we also discovered that Y. pestis manipulation of Rab11b disrupts global endocytic recycling in the macrophage. Together these data suggest the hypothesis that Y. pestis specifically targets and recruits Rab11 to the YCV to avoid phagolysosome maturation and generate a replicative niche within macrophages. Furthermore, we hypothesize that disruption of cellular trafficking during the YCV biogenesis process also disrupts TLR-4 trafficking and immune signaling during intracellular infection. Here we propose to expand on these initial findings to further define how Y. pestis manipulates Rab11 and the host recycling machinery to generate the YCV. Specifically, we will answer two key questions. First, how does Y. pestis recruit Rab11 to the YCV (Aim 1)? Second, how does Rab11 recruitment impact the remodeling of the YCV (Aim 2)? Specifically, what other components of the recycling pathway does Rab11 recruit to the YCV and do these components directly contribute to YCV biogenesis and intracellular survival? Furthermore, as TLR-4 recruitment to the phagosome is dependent on Rab11, how does YCV biogenesis and Rab11 manipulation by Y. pestis impact TRL-4 trafficking and inflammatory signaling? Answering these questions will fill a critical gap in our understanding of how Y. pestis is able to subvert normal phagosome maturation and survive within this intracellular niche. Furthermore, through understanding how Y. pestis manipulates the host recycling and inflammatory pathways we can gain novel insight into the interactions between these pathways in the context of normal cell biology.