Jiangsu Key Laboratory of Infection and Immunity, Institute of Biology and Medical Sciences, Soochow University, Postal address: 199 Renai Road, SIP, Suzhou, Jiangsu, China.
Tuberculosis (Edinb). 2019 May;116:22-31. doi: 10.1016/j.tube.2019.03.010. Epub 2019 Apr 4.
Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mtb), leading to about a million deaths each year. EspR is a DNA binding protein of Mtb which regulates expression of multiple genes and the activity of ESX-1 secretion system of the bacteria, with itself being secreted out as a substrate of ESX-1. We explored the function of secreted EspR in host cells by overexpressing the protein in murine macrophage cell line RAW264.7, infecting the cells with BCG which does not secrete EspR, and evaluating the antimicrobial responses of the cells. We found that EspR resulted in an increased intracellular bacteria load in macrophages. This is due to its inhibition on BCG induced expression of inflammatory cytokines and inducible nitric oxide synthase (iNOS), as well as host cell apoptosis. Mechanism study showed that EspR directly interacted with adaptor protein myeloid differentiation factor 88 (MyD88), suppressed MyD88 dependent Toll-like receptor (TLR) and IL-1R signal activation, thus reduced inflammatory responses and apoptosis in macrophages and promoted mycobacteria survival.
结核病是由结核分枝杆菌（Mtb）引起的传染病，每年导致约 100 万人死亡。EspR 是 Mtb 的一种 DNA 结合蛋白，可调节多个基因的表达和细菌 ESX-1 分泌系统的活性，自身作为 ESX-1 的底物被分泌出来。我们通过在鼠巨噬细胞系 RAW264.7 中过表达该蛋白，感染不分泌 EspR 的 BCG 来研究分泌型 EspR 在宿主细胞中的功能，并评估细胞的抗菌反应。我们发现 EspR 导致巨噬细胞中的胞内细菌负荷增加。这是由于其抑制 BCG 诱导的炎性细胞因子和诱导型一氧化氮合酶（iNOS）的表达，以及宿主细胞凋亡。机制研究表明，EspR 直接与衔接蛋白髓样分化因子 88（MyD88）相互作用，抑制 MyD88 依赖性 Toll 样受体（TLR）和 IL-1R 信号激活，从而减少巨噬细胞中的炎症反应和细胞凋亡，并促进分枝杆菌的存活。
