Dendritic cell targeting by bacterial LysM proteins to suppress inflammation

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Project Summary Inflammation is an evolutionarily conserved reaction with both beneficial and detrimental impacts on health. Excessive and prolonged inflammatory responses can promote damage to host tissues and contribute to numerous chronic human diseases while inadequate inflammation promotes susceptibility to infection. It is still not clear how the balance of these pro-and anti-inflammatory factors is determined and thus why inflammation persists and becomes chronic in some contexts, but not others. Due to the antimicrobial effects of inflammation, microbes have evolved strategies to interfere with the inflammatory response. Our published and preliminary studies have provided evidence that a secreted Listeria monocytogenes (Lm) virulence-promoting protein (p60) specifically targets the cDC1 subset of dendritic cells to promote the production of IL-10 by NK cells. IL-10 is a cytokine important for resolution of inflammation. Our proposed studies will dissect the mechanisms by which a specific domain present in p60 as well as proteins from numerous other bacteria acts to induce this response. Specifically, we investigate how newly identified receptors promote the response to p60, how p60 acts once in the cell, and unique features of p60 that support it ability to manipulate immune responses.