Intracellular IL-17 signaling during Coxiella burnetii infection

伯氏柯克斯体感染过程中细胞内 IL-17 信号转导

基本信息

批准号：
10063664
负责人：
STACEY D GILK
金额：
$ 1.36万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2020-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063664
关键词：
Acute Adaptor Signaling Protein Alveolar Macrophages Antibiotic Therapy Bacteria Bacterial Infections Bacterial Proteins Binding Biological Assay CXCL2 gene Cell physiology Cells Chemotaxis Chronic Disease Communicable Diseases Coxiella Coxiella burnetii Cytoplasm Data Disease Disease Progression Down-Regulation Etiology Future Genes Genetic Transcription Hour Human IL17 Signaling Pathway Immune response Immunoblotting In Vitro Infection Inflammatory Inflammatory Response Innate Immune Response Innate Immune System Interleukin-17 Knock-out Knowledge Libraries Lung Lung infections MAPK Signaling Pathway Pathway Membrane Methods Modeling Molecular Mus Neutrophil Infiltration Pathogenesis Pathway interactions Phagolysosome Play Process Proteins Publishing Q Fever RANTES Research Role Signal Pathway Signal Transduction Site Surface System TRAF6 gene Testing Transcriptional Activation Vacuole Virulence base chemokine cytokine disorder control experimental study in vivo inhibitor/antagonist macrophage mouse model mutant neutrophil new therapeutic target novel strategies pathogen receptor recruit screening therapeutic target ubiquitin-protein ligase

项目摘要

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.

项目概要/摘要伯内特柯克斯体是一种专性细胞内细菌，也是 Q 热的病原体。自然感染期间柯克斯体以肺泡巨噬细胞为目标，在其中促进吞噬溶酶体样的形成液泡称为含有柯克斯体的液泡（CCV）。成功的宿主细胞感染需要 IVB 型分泌系统 (T4BSS)，可将细菌效应蛋白穿过 CCV 膜并进入宿主细胞质，它们操纵各种细胞过程。我们最近证明了 Coxiella T4BSS 下调 IL-17 靶基因以及 IL-17 刺激的趋化因子的表达分泌。 IL-17 是一种促炎细胞因子，在先天免疫反应中发挥关键作用肺部病原体。 IL-17 结合后，巨噬细胞表面 IL-17 受体激活多种细胞内通过 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。所提出的实验将检验我们的假设，即 Coxiella T4BSS 效应子蛋白质下调细胞内 IL-17 信号通路以逃避宿主先天免疫反应并促进细菌发病。目标 1 将确定参与的宿主和细菌蛋白 IL-17 触发细胞内 ACT1-TRAF6 信号通路的下调。目标 2 将阐明其作用 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念珠菌的特定宿主先天免疫反应，也是病原体在初始阶段逃避免疫反应所采用的一种新策略感染。