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

Mtb 毒力因子直接激活 TGFbeta 以抑制 CD4 T 细胞反应

• 批准号: 10374127
• 负责人: Christoph Grundner
• 金额: $ 23.56万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-20 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374127
• 关键词: Ablation; Active Sites; Affect; Biochemical; CD4 Positive T Lymphocytes; Cell physiology; Cellular Immunity; Chemicals; Clinical; Complement Factor B; Environment; Enzyme-Linked Immunosorbent Assay; Enzymes; Exclusion; Failure; Filtration; Granuloma; Growth; Human; Immune; Immune response; Immune system; Immunity; In Vitro; Infection; Interferon Type II; Interferons; Ion-Exchange Chromatography Procedure; Kinetics; Label; Lung; Mass Spectrum Analysis; Modeling; Mus; Mycobacterium tuberculosis; Outcome; Pathogenesis; Pathway interactions; Patients; Process; Production; Proteins; Recombinants; Resolution; Role; Sampling; Series; Serine Hydrolase; Serine Protease; Signal Transduction; Site; Structure; T cell response; T-Cell Activation; T-Lymphocyte; TCF Transcription Factor; Testing; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Transforming Growth Factors; Tuberculosis; Vaccination; Virulence Factors; Work; base; cytokine; experimental study; imaging approach; improved; in vitro activity; inhibitor; loss of function; mouse model; mutant; new therapeutic target; novel therapeutic intervention; pathogen; pulmonary granuloma; response; single cell analysis; spatial relationship; tuberculosis granuloma; tuberculosis immunity

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.

项目摘要 结核分枝杆菌（Mtb）通过分泌一系列毒力因子来促进其存活， 免疫力因此，对结核病（TB）的保护性免疫非常难以实现，无论是通过 接种疫苗或自然感染。有效的CD 4 T细胞应答是预防TB的一个明确相关因素 导致产生干扰素γ（IFN γ）。然而，一个长期存在的问题是，为什么即使是一个强大的 IFN γ应答不能有效地控制肺中感染部位的Mtb。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Mtb- 特异性T细胞被系统地从这些最需要它们的部位排除。而 这种空间排斥的机制尚未完全了解，免疫抑制细胞因子转化 生长因子（TGF）正在成为结核病T细胞颠覆的一个有效因素。TGF β强烈共定位 与肉芽肿中的Mtb，表明Mtb可能直接激活TGF β破坏这种微环境， 使CD 4 T细胞功能丧失，并消除IFN γ信号传导。我们现在发现结核分枝杆菌裂解物和培养滤液 蛋白质确实可以有效地从其惰性的潜在前体激活TGF β。这种活性是热不稳定的， 被Mtb感染，并被丝氨酸水解酶抑制剂抑制。在这里，我们将测试结核分枝杆菌分泌一种 一种丝氨酸蛋白酶毒力因子，直接加工并激活TGF β 1以抑制生产性CD 4 T细胞 Mtb感染部位的活化。本项目旨在确定一种新的和直接的宿主-pathgen相互作用 以及Mtb发病机制，其是免疫系统无法控制Mtb感染的基础。