Manipulation of the host cell inflammasome by Mycobacterium tuberculosis

结核分枝杆菌对宿主细胞炎症小体的操纵

基本信息

批准号：
10619641
负责人：
VOLKER BRIKEN
金额：
$ 58.52万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-08 至 2026-05-31
项目状态：
未结题

项目摘要

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.

抽象的仅 2017 年，结核分枝杆菌 (Mtb) 就导致人类患上结核病 (TB)。报告了约 1000 万新病例，导致约 130 万人死亡。存在有效的结核病疫苗和次优化疗药物。IL-1 是一种细胞因子。增加宿主对 Mtb 感染的抵抗力，能够限制 IL-1 的产生量。通过抑制宿主细胞炎症小体的激活，我们对 Mtb 如何理解存在差距。利用宿主细胞信号传导来抑制炎症小体的激活。 Mtb 首次能够抑制 NLRP3 炎症小体的激活，我们发现了第一个 Mtb 基因 (PknF) 对于这种抑制很重要，我们进行了功能获得性遗传筛选并进行了研究。我们确定了 Mtb 的其他 5 个基因组区域介导 AIM2 炎症小体的抑制。认为特定Mtb基因的发现参与抑制宿主炎症小体激活（具体目标 1）将允许表征抑制的分子机制（具体目标目标 2) 并测试其对 Mtb 毒力的重要性（具体目标 3）。我们相信，我们的研究结果将具有巨大的转化潜力，因为它具有更大的意义。了解宿主细胞炎症小体激活的分子机制将提供开发辅助结核病药物和针对宿主的治疗方法的新靶点。