Manipulation of the host cell inflammasome by Mycobacterium tuberculosis

摘要 结核分枝杆菌(Mtb)可引起人类肺结核(TB)。仅在2017年， 报告新增病例约1000万例，导致约130万人死亡。没有 目前存在有效的结核病疫苗和次佳的化疗药物。IL-1是一种细胞因子 增强宿主对结核杆菌感染的抵抗力。结核分枝杆菌能够限制IL-1的生成量 通过抑制宿主细胞炎性小体的激活。我们对结核分枝杆菌是如何 利用宿主细胞信号来抑制炎症体的激活。我们描述的是 首次发现Mtb可以抑制NLRP3炎症体的激活，我们首次发现了 MTB基因(PnuF)对这种抑制作用起重要作用。我们进行了功能获得基因筛查 确定了Mtb的另外5个基因组区域，它们介导了对AIM2炎症体的抑制。我们 认为特异性Mtb基因的发现参与了抑制宿主炎症小体的激活 (特定目标1)将能够描述抑制(特定目标)的分子机制 目标2)和测试它们对结核分枝杆菌毒力的重要性(特定目标3) 研究提案。我们相信，我们的发现将具有巨大的翻译潜力，因为 了解宿主细胞炎性小体激活的分子机制将有助于 开发辅助结核分枝杆菌药物和宿主导向疗法的新靶点。

Abstract Mycobacterium tuberculosis (Mtb) causes pulmonary tuberculosis (TB) in humans. In 2017 alone, ~10.0 million new cases were reported, leading to approximately ~1.3 million deaths. There are no effective vaccines for TB and only sub-optimal chemotherapeutics exist. IL-1 is a cytokine that increases host resistance against Mtb infections. Mtb is able to limit the amount of IL-1 production by inhibiting the host cell inflammasome activation. There is a gap in our understanding of how Mtb exploits host cell signaling in order to inhibit the activation of the inflammasome. We describe for the first time that Mtb can inhibit the activation of the NLRP3 inflammasome and we identified the first Mtb gene (PknF) important for this inhibition. We performed a gain-of-function genetic screen and identified 5 other genomic regions of Mtb mediating the inhibition of the AIM2 inflammasome. We think that the discovery of specific Mtb genes involved in inhibiting the host inflammasome activation (Specific Aim 1) will allow for the characterization of the molecular mechanisms of inhibition (Specific Aim 2) and for testing their importance for virulence of Mtb (Specific Aim 3) during the course of the research proposal. We believe that our findings will have great translational potential since a greater understanding of the molecular mechanisms of host cell inflammasome activation will provide novel targets for development of adjunctive Mtb drugs and of host-directed therapeutics.