Genetic Analyses of bacteremia non-typhoidal Salmonella

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Project Summary There are at least 3.4 million cases of bacteremia with invasive non-typhoidal Salmonella per year that result in 680,000 deaths1. Despite its significant cost on human health with a 20% fatality rate, bacteremia caused by this pathogen is poorly understood. One important class of virulence factors is ones that are anti-inflammatory. Traditionally, such genes were thought to promote virulence by attenuating anti-microbial mechanisms such as intracellular killing and the induction of apoptosis. My undergraduates surprisingly discovered that one of dozens of such effectors, SpvC, is instead required for extraintestinal dissemination by interdicting the host's ability to control the movement of infected phagocytes. They developed an in vitro cell c0-culture assay that models the traversal of the blood vascular endothelium by phagocytes in the basal to apical direction that before their work had only been observed with uninfected cells, a process that immunologists refer to as reverse transmigration. The long-term goal of this work is to develop new therapeutic intervention strategies for compartmentalizing infections, thereby greatly reducing their chance of lethality. The short-term objective of this work is to characterize how microbial and host factors regulate the extraintestinal dissemination of invasive non- typhoidal Salmonella. In the first aim, with two in vitro models we will test a detailed molecular mechanism that accounts for the ability of SpvC to promote movement. In the second aim, we quantify how much each of the known pathways of extraintestinal dissemination contribute to systemic disease and assess the role of SpvC in each. We hypothesize that the phosphothreonine lyase activity of SpvC deactivates three MAPK kinases, to down regulate the host cytokine MIF, which normally potently inhibits phagocyte movement. We will test if this prevents Salmonella from disseminating through both the lymphatic system and the reverse transmigration pathways.