RP4: Harnessing autophagy to treat tuberculosis

项目总结--报告4 结核分枝杆菌仍然是最具破坏性的人类传染病之一，造成200万人死亡。 每年死亡人数占世界人口的三分之一，而且是潜伏性感染。结核分枝杆菌最近进化成 对多种一线抗生素产生抗药性，因此，开发有助于杀死 需要耐药的结核分枝杆菌。其中一种方法是细菌无法进化出抵抗力 是开发利用宿主反应的治疗方法，增强人体自身的系统以杀死M。 肺结核。宿主过程称为降解自噬，细胞通过这种过程吞噬并降解细胞内。 细菌最近成为宿主导向治疗的可能靶点。在前一届CETR中，与 RP1-3，我们鉴定了几个可以利用自噬途径限制M。 巨噬细胞和体内的结核复制。我们还发现了一些分子机制， 自噬启动，细菌被定为降解的目标。具体地说，在结核分枝杆菌感染期间， 胞质DNA被cGAS和STING蛋白检测到，导致自噬启动，而M。 结核病是泛素连接酶S-1降解的靶标。此外，我们还发现，一个核心 自噬蛋白ATG5抑制结核分枝杆菌病理性中性粒细胞炎症 感染。因此，在拟议的研究中，我们将(1)测试自噬导向化合物对 临床前模型中的结核分枝杆菌，(2)cGAS-stest依赖的定义和靶向机制 结核分枝杆菌感染过程中自噬的激活，(3)确定和靶向M。 结核通过S-1和(4)以自噬小体为靶标，定义和靶向参与 ATG5介导的结核分枝杆菌感染中性粒细胞炎症的控制。我们预料到 这些方法将导致对先导化合物的鉴定，为未来的研究建立新的广泛的 光谱抗感染药物。

PROJECT SUMMARY – RP4 Mycobacterium tuberculosis remains one of the most devastating human infectious diseases, causing two million deaths annually and latently infecting a third of the world’s population. M. tuberculosis has recently evolved to become resistant to multiple first-line antibiotics, and as such, developing approaches to facilitate the killing of drug-resistant M. tuberculosis are needed. One such approach for which the bacteria cannot evolve resistance is to develop therapeutics that harness the host response, enhancing the body’s own systems for killing M. tuberculosis. The host process called degradative autophagy by which cells engulf and degrade intracellular bacteria has recently emerged as a possible target for host-directed therapy. In the prior CETR, together with RP1-3, we identified and characterized several molecules that can harness the autophagy pathway to restrict M. tuberculosis replication in macrophages and in vivo. We also discovered molecular mechanisms by which autophagy is initiated and bacteria targeted for degradation. Specifically, during M. tuberculosis infection, cytoplasmic DNA is detected by the proteins cGAS and STING, leading to autophagy initiation, while M. tuberculosis is targeted for degradation by the ubiquitin ligase Smurf1. In addition, we discovered that a core autophagy protein, ATG5, suppressed pathologic neutrophilic inflammation in the context of M. tuberculosis infection. Thus, in the proposed research we will (1) Test autophagy-directed compounds for activity against M. tuberculosis in preclinical models, (2) Define and target mechanisms of cGAS-STING-dependent autophagy activation during M. tuberculosis infection, (3) Define and target mechanisms by which M. tuberculosis is targeting to autophagosomes by Smurf1 and (4) Define and target pathways involved in ATG5-mediated control of neutrophilic inflammation during M. tuberculosis infection. We anticipate that these approaches will result in identification of lead compounds for future studies to establish new broad- spectrum anti-infectives.