结核分枝杆菌VII型分泌系统ESX-1中EspA/EspC参与毒力因子ESAT-6/CFP-10分泌的分子机制研究

VII型分泌系统ESX-1在结核分枝杆菌（MTB）致病过程中扮演着重要角色,其通过分泌重要的毒力蛋白ESXA(EAST-6)和ESXB(CFP-10)等裂解宿主巨噬细胞，进而引发MTB的侵袭和播散，但毒力蛋白分泌到胞外的分子机制尚未阐明。已有研究证实ESX-1系统的espACD基因簇编码的蛋白EspA/EspC为ESXA/B分泌所必需。我们前期研究发现在胞质中EspA作为EspC的伴侣蛋白，二者在胞质中以二聚体形式发挥作用。为明确EspA/EspC在ESX-1中的重要作用，揭示EspA/EspC参与ESXA/B分泌的分子机制，本研究拟应用结构生物学、生物化学、生物物理学和细菌学等技术，通过解析EspA/EspC单体和复合物结构、结合体内外分泌试验阐明EspA/EspC在ESXA/B分泌中的分子机制。此机制的阐明将为以ESXA/B为靶点的药物设计和疫苗的开发提供强有力的科技支撑。

The T7SS/ ESX-1 plays an important role in the pathogenesis of Mycobacterium tuberculosis (MTB),which exports virulence factors ESXA(EAST-6) and ESXB(CFP-10) involving in macrophage invasive, phagosome escape and intercellular spread. However, the molecular mechanisms of the secretion of ESXA/B were still unknown. Previous studies showed that espA and espC, located in espACD gene cluster which was unlinked to ESX-1, yet it was essential for ESXA/ESXB secretion. Our preliminary work identified EspC associated with its chaperone EspA in the cytosol involving the secretion of ESXA/B. In order to elucidate the molecular mechanisms relating to EspA/EspC cosecreted with ESXA/B , our study will present a structural and functional characterization of EspA/EspC utilizing the methods of structural biology, biochemistry, biophysics and bacteriology, highlighting crystal structure and cryo-electron microscopy technique. Taken together, our work will definitely contribute for the design of new antituberculosis drug and vaccine targeting ESXA/B .