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

• 批准号: 10201507
• 负责人: STACEY D GILK
• 金额: $ 19.13万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201507
• 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; respiratory pathogen; screening; therapeutic target; ubiquitin-protein ligase

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.

项目总结/摘要 贝氏柯克斯体是一种专性胞内细菌，是Q热的病原体。在自然感染过程中 柯克斯体以肺泡巨噬细胞为目标，在那里细菌促进吞噬溶酶体样蛋白的形成。 空泡称为Coxiella Containing cycloole（CCV）。成功的宿主细胞感染需要IVB型 分泌系统（T4 BSS），其将细菌效应蛋白易位穿过CCV膜并进入CCV中。 宿主细胞质，在那里它们操纵各种细胞过程。我们最近证明， Coxiella T4 BSS下调IL-17靶基因以及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，其在针对肿瘤的先天性免疫应答中具有关键作用。 肺部病原体在IL-17结合后，巨噬细胞表面IL-17受体激活几种细胞内的 通过E3-泛素连接酶ACT 1的信号通路。ACT 1泛素化TRAF 6，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 T4 BSS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应答 并促进细菌致病。目的1将确定宿主和细菌蛋白参与 IL-17触发的细胞内ACT 1-TRAF 6信号通路下调。目标2将阐明 IL-17信号在趋化因子分泌和嗜中性粒细胞募集到考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一种特异性的宿主先天免疫应答用于对抗C。伯内特氏菌， 也是病原体在感染的初始阶段逃避免疫反应的一种新策略， 感染