Intracellular IL-17 signaling during Coxiella burnetii infection

项目摘要/摘要 伯氏柯克斯体是Q热的专性胞内细菌，是Q热的病原体。在自然感染期间 柯克斯体以肺泡巨噬细胞为靶标，在肺泡巨噬细胞中，该细菌促进形成类吞噬溶酶体。 液泡称为含有柯克斯氏菌的液泡(CCV)。成功的宿主细胞感染需要IVB型 分泌系统(T4BSS)，它将细菌效应蛋白跨CCV膜转移到 宿主细胞质，在那里它们操纵各种细胞过程。我们最近展示了 柯克斯体T4BSS下调IL-17靶基因和IL-17刺激的趋化因子的表达 分泌物。IL-17是一种促炎细胞因子，在先天性免疫反应中起关键作用。 肺部病原体。在IL-17结合后，巨噬细胞表面的IL-17受体激活了几个细胞内 通过E3-泛素连接酶ACT1的信号通路。Act1泛素化TRAF6，触发转录 IL-17靶基因的激活。拟议的实验将检验我们的假设，柯克斯体T4BSS效应器 蛋白质下调细胞内IL-17信号通路(S)以逃避宿主天然免疫反应 并促进细菌致病。目标1将确定宿主和参与其中的细菌蛋白 IL-17对细胞内ACT1-TRAF6信号通路的下调作用目标2将阐明这一角色 IL-17信号在趋化因子分泌和中性粒细胞募集到柯克斯体感染的巨噬细胞中的作用。 这些研究的完成不仅将揭示针对伯氏梭菌的特定宿主先天免疫反应， 也是病原体在发病初期逃避免疫反应的一种新策略 感染。

PROJECT SUMMARY/ABSTRACT Coxiella burnetii is an obligate intracellular bacterium and the etiological agent of Q fever. During natural infection Coxiella targets alveolar macrophages, where the bacterium promotes formation of a phagolysosome-like vacuole called the Coxiella Containing Vacuole (CCV). Successful host cell infection requires the Type IVB Secretion System (T4BSS), which translocates bacterial effector proteins across the CCV membrane and into the host cytoplasm, where they manipulate a variety of cell processes. We recently demonstrated that the Coxiella T4BSS downregulates expression of IL-17 target genes as well as IL-17-stimulated chemokine secretion. IL-17 is a pro-inflammatory cytokine that has a key role in the innate immune response against pulmonary pathogens. Upon IL-17 binding, the macrophage surface IL-17 receptor activates several intracellular signaling pathways through the E3-ubiquitin ligase ACT1. ACT1 ubiquitinates TRAF6, triggering transcriptional activation of IL-17 target genes. The proposed experiments will test our hypothesis that Coxiella T4BSS effector proteins downregulate intracellular IL-17 signaling pathway(s) in order to evade the host innate immune response and promote bacterial pathogenesis. Aim 1 will determine the host and bacterial proteins involved in downregulation of intracellular ACT1-TRAF6 signaling pathways triggered by IL-17. Aim 2 will elucidate the role of IL-17 signaling in chemokine secretion and neutrophil recruitment to Coxiella-infected macrophages. Completion of these studies will not only reveal a specific host innate immune response used against C. burnetii, but also a novel strategy employed by pathogens to escape the immune response during the initial stages of infection.