Dendritic cell targeting by bacterial LysM proteins to suppress inflammation

项目摘要 炎症是一种进化上保守的反应，对健康既有有益的影响，也有有害的影响。 过度和长期的炎症反应可促进对宿主组织的损伤，并有助于 许多慢性人类疾病，而炎症不足会促进对感染的易感性。它仍然是 尚不清楚这些促炎因子和抗炎因子的平衡是如何确定的， 在某些情况下会持续存在并成为慢性病，但在其他情况下则不然。由于炎症的抗菌作用， 微生物已经进化出干扰炎症反应的策略。我们已公布的和初步的 研究提供了证据表明，分泌的单核细胞增生李斯特菌（Lm）毒力促进蛋白（p60） 特异性靶向树突细胞的cDC 1亚群，以促进NK细胞产生IL-10。IL-10是 细胞因子对炎症的消退很重要。我们提出的研究将剖析机制， 存在于p60中的特定结构域以及来自许多其它细菌的蛋白质起诱导这种应答的作用。 具体来说，我们研究了新发现的受体如何促进对p60的反应，p60如何在细胞内发挥作用。 细胞，以及支持其操纵免疫反应能力的p60的独特特征。

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.