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: 10295139
• 负责人: STACEY D GILK
• 金额: $ 18.45万
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10295139
• 关键词: Intracellular; IL; 17; signaling; during

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 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. Further, the Coxiella T4BSS confers protection against IL-17 mediated killing by the macrophage. 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. Unphosphorylated ACT1 ubiquitinates TRAF6, triggering transcriptional activation of IL-17 target genes, while phosphorylated ACT1 recruits TRAF2/5, binds to the 3’ mRNA of IL-17 target genes and stabilizes the mRNA for translation. 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 whether Coxiella targets the ACT1-TRAF6 pathway to downregulate IL-17 target gene transcription. Aim 2 will test whether Coxiella destabilizes the mRNA of IL-17 target genes through ACT1-TRAF2/5. 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.

项目摘要/摘要 Coxiella burnetii是一种强制性细胞内细菌，也是Q发烧的病因。在自然感染期间 Coxiella靶向肺泡巨噬细胞，其中细菌促进了吞噬体样形成 液泡称为含液泡（CCV）的液泡。成功的宿主细胞感染需要IVB型 分泌系统（T4BSS），将细菌效应子蛋白跨CCV膜转移到 宿主细胞质，在其中操纵各种细胞过程。我们最近证明了柯西埃拉 T4BS下调IL-17靶基因的表达以及IL-17刺激的趋化因子分泌。 此外，Coxiella T4BSS防止巨噬细胞介导的IL-17介导的杀戮。 IL-17是一个亲 炎性细胞因子在对肺病原体的先天免疫反应中具有关键作用。之上 IL-17结合，巨噬细胞表面IL-17受体激活几种细胞内信号通路 E3-泛素连接酶ACT1。未磷酸化的ACT1泛素化Traf6，触发转录激活 IL-17靶基因的磷酸化ACT1募集TRAF2/5的靶基因与IL-17靶基因的3'mRNA结合 并稳定mRNA进行翻译。提出的实验将检验我们的假设，即Coxiella！t4bss 效应子蛋白下调细胞内IL-17信号通路（S），以逃避宿主先天免疫 反应并促进细菌发病机理。 AIM 1将确定Coxiella是否针对ACT1-TRAF6 下调IL-17靶基因转录的途径。 AIM 2将测试Coxiella是否破坏mRNA的稳定 通过ACT1-TRAF2/5的IL-17靶基因这些研究的完成不仅会揭示特定的宿主 对伯内特氏梭菌的先天免疫反应，但也是病原体采用的一种新型策略来逃脱 在感染初始阶段的免疫反应。