非质子泵细胞色素bd氧化酶介导结核菌逃逸宿主IFNγ应答的作用和机制

IFNγ应答是宿主限制细胞内结核菌增殖的重要机制。然而结核菌具有快速适应宿主坏境存活的能力，即使在IFNγ信号通路正常的宿主中，结核菌也被彻底清除。那么，结核菌是如何逃逸宿主IFNγ免疫杀伤？我们利用转座子插入突变文库测序发现结核菌编码呼吸链末端非质子泵细胞色素bd氧化酶亚基基因（CydA）的突变株在IFNγ活化的巨噬细胞中丰度显著降低；进一步验证发现IFNγ活化的巨噬细胞可以显著杀伤CydA基因敲除株，这种杀伤作用并不依赖于宿主细胞ROS/RNS；而是跟CydA基因缺陷导致结核菌对酸性更加敏感相关。因此，我们推测结核菌在IFNγ诱导巨噬细胞吞噬体酸性条件中，主要是依赖于细胞色素bd氧化酶来维持细菌的呼吸作用，逃逸宿主杀伤。本项目拟进一步研究细胞色素bd氧化酶在IFNγ诱导吞噬体酸性条件下，如何调控结核菌的呼吸作用来帮助结核菌抵抗宿主免疫杀伤，从而为结核病新型疫苗和/或药物研发提供新思路。

IFNγ response is an important mechanism to limit the proliferation of Mycobacterium tuberculosis (Mtb). However, Mtb has the ability to adapt to the host environment to survive. The host could only limit the growth of Mtb with the help of IFNγ. How Mtb escapes from host IFNγ-mediated immunity? Using transposon insertion library sequencing, we found that a transposon insertion in CydA, encoding a subunit of non-proton pump cytochrome bd oxidase were significantly reduced in the IFNγ-activated macrophages. IFNγ-activated macrophages macrophages can significantly kill the cydA knockout strain independent on ROS/RNS signaling. Further study revealed that genetic knockout cydA was defective for growth at low pH. Therefore, we speculate that cytochrome bd oxidase is important for Mtb to maintain the bacteria's respiratory under IFNγ-induced phagocytosis acidification. This project intends to clarify the mechanism by which IFNγ increases bacterial dependence of on cytochrome bd oxidase and how Mtb uses cytochrome bd oxidase to help itself escapes from host IFNγ-mediated immunity.The completion of the project will provide new strategies for the development of new vaccines and/or drugs for tuberculosis.