全球耐药结核病疫情严峻，急需探寻抗结核新药靶。自噬在结核分枝杆菌（Mtb）感染中是一把“双刃剑”，一方面自噬有助于清除细胞内的Mtb，另一方面自噬也可被Mtb所干扰或利用并最终促进Mtb的胞内存活。目前有关Mtb中调控宿主自噬的病原因子及机制远未明确。我们的前期研究结果提示一系列Mtb病原因子包括Mtb PtpA、PknG和Rv1468c等可调控自噬过程的多个节点并影响病原菌的胞内存活。在本项目中，我们拟深入探寻上述Mtb病原因子通过与特定宿主因子互作进而调控宿主细胞自噬发生、自噬体形成和自噬体成熟等过程的分子机制，主要研究内容包括：1）PtpA和PknG诱导宿主细胞自噬发生的机制；2）Rv1468c促进宿主细胞自噬体形成的机制；3）PknG抑制宿主细胞自噬体成熟的机制；4）Mtb中可调控细胞自噬过程的新病原因子的鉴定及功能研究。该项目将为针对自噬过程的抗结核治疗提供理论基础和潜在新靶标。

Facing the severe situation of drug-resistant tuberculosis worldwide, it is urgent for us to identify novel anti-tuberculosis drug targets. Autophagy serves as a double-edged sword during Mycobacterial tuberculosis (Mtb) infection. On the one hand, autophagy facilitates the clearance of intracellular Mtb. On the other hand, Mtb could subvert or hijack host autophagy to facilitate its intracellular survival. Currently, the specific Mtb pathogenic factors responsible for regulating host autophagy as well as the underlying molecular mechanisms remains largely unclear. Results from our preliminary studies suggest that a number of Mtb pathogenic factors including Mtb PtpA, PknG and Rv1468c could regulate multiple stages of host autophagy to affect the intracellular survival of the pathogen. In this project, we will investigate the molecular mechanisms by which the above-mentioned Mtb pathogenic factors interact with certain host factors to manipulate specific stages of autophagy such as induction of autophagy, autophagosome formation, as well as phagosome maturation. The main research contents in this project include: 1) The mechanism by which PtpA and PknG induce autophagy; 2) The mechanism by which Rv1468c promotes autophagosome formation; 3) The mechanism by which PknG inhibits phagosome maturation; 4) Identification of novel Mtb pathogenic factors that regulate host autophagy process and investigation of their functions. Results from this project would provide theoretical basis and novel potential targets for the treatment of tuberculosis.