Direct activation of TGFbeta by an Mtb virulence factor to suppress CD4 T-cell responses

项目总结 结核分枝杆菌(Mtb)通过分泌一系列毒力因子促进其存活。 豁免权。因此，对结核病(TB)的保护性免疫是极其困难的，无论是通过 接种疫苗或自然感染。预防结核病的一个明显的相关性是有效的CD4T细胞反应 这会导致干扰素的产生。然而，一个长期存在的问题是，为什么即使是一个强大的 干扰素应答不能有效控制肺部感染部位的结核分枝杆菌。最近的研究表明， 肺，特别是肉芽肿，是一个免疫抑制的环境，最具保护性的结核分枝杆菌- 特定的T细胞被系统地排除在这些最需要它们的部位之外。而当 这种空间排斥的机制还不完全清楚，免疫抑制细胞因子转化 生长因子(转化生长因子)正在成为结核病中T细胞颠覆的有力因素。转化生长因子强烈共定位 肉芽肿中有结核分枝杆菌，提示结核分枝杆菌可能直接激活转化生长因子，破坏这种微环境， 禁用CD4T细胞功能，阻断干扰素信号。我们现在展示了结核分枝杆菌裂解物和培养滤液 蛋白质确实能有效地从其惰性潜伏前体中激活转化生长因子。这种活性是热不稳定的，分泌的。 通过Mtb，并被丝氨酸水解酶抑制剂抑制。在这里，我们将检验以下假设：结核分枝杆菌分泌 直接处理和激活转化生长因子以抑制产生CD4T细胞的丝氨酸蛋白酶毒力因子 结核分枝杆菌感染部位的激活。该项目旨在确定一种新的、直接的宿主-病原体相互作用 以及导致免疫系统无法控制结核分枝杆菌感染的结核分枝杆菌发病机制。

PROJECT SUMMARY Mycobacterium tuberculosis (Mtb) promotes its survival by secreting a range of virulence factors that modulate immunity. As a result, protective immunity to tuberculosis (TB) is exceedingly difficult to achieve, whether by vaccination or natural infection. One clear correlate of protection from TB is an effective CD4 T cell response that leads to production of interferon gamma (IFN. However, a long-standing question is why even a robust IFN response fails to effectively control Mtb at the site of infection in the lung. Recent work has shown that the lung, and in particular the granuloma, is an immunosuppressive environment and that the most protective Mtb- specific T cells are systematically excluded from these sites where they are needed the most. While the mechanisms for this spatial exclusion are not fully understood, the immunosuppressive cytokine transforming growth factor  (TGF is emerging as a potent factor of T cell subversion in TB. TGF strongly co-localizes with Mtb in the granuloma, suggesting that Mtb may directly activate TGF to subvert this microenvironment, disable CD4 T cell function, and extinguish IFN signaling. We now show that Mtb lysate and culture filtrate protein can indeed effectively activate TGF from its inert latent precursor. This activity is heat-labile, secreted by Mtb, and is inhibited by serine hydrolase inhibitors. Here, we will test the hypothesis that Mtb secretes a serine protease virulence factor that directly processes and activates TGF to suppress productive CD4 T cell activation at the site of Mtb infection. This project aims to identify a new and direct host-pathgen interaction and a mechanism of Mtb pathogenesis that underlies the immune system’s failure to control Mtb infection.