Manipulation of the host cell inflammasome by Mycobacterium tuberculosis

摘要 结核分枝杆菌（Mtb）在人类中引起肺结核（TB）。仅在2017年， 报告了约1000万例新病例，导致约130万例死亡。没有 有效的结核病疫苗和仅存在次优的化学治疗剂。IL-1 β是一种细胞因子， 增加宿主对Mtb感染的抵抗力。结核分枝杆菌能够限制IL-1 β的产生量， 通过抑制宿主细胞炎性小体的活化。我们对结核病如何传播 利用宿主细胞信号传导以抑制炎性小体的活化。我们描述了 这是Mtb第一次能够抑制NLRP 3炎性体的激活，我们首次鉴定了Mtb的抑制作用。 Mtb基因（PknF）对这种抑制作用很重要。我们进行了功能获得性基因筛查， 鉴定了Mtb介导AIM 2炎性体抑制的5个其他基因组区域。我们 我认为，发现特异性Mtb基因参与抑制宿主炎性小体激活 （特异性目标1）将允许表征抑制的分子机制（特异性 目的2），并测试其对结核分枝杆菌毒力的重要性（具体目的3）， 研究提案。我们相信，我们的发现将具有巨大的转化潜力，因为 对宿主细胞炎性小体激活的分子机制的理解将提供 开发抗结核药物和宿主导向治疗的新靶点。

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.