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: 10191677
• 负责人: Christoph Grundner
• 金额: $ 28.28万
• 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/10191677
• 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/antagonist; 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.

项目概要 结核分枝杆菌 (Mtb) 通过分泌一系列调节毒力的因子来促进其生存 因此，无论是通过什么途径，都很难获得对结核病（TB）的保护性免疫力。 预防结核病的一个明显相关因素是有效的 CD4 T 细胞反应。 导致产生干扰素γ（IFN）。然而，一个长期存在的问题是，为什么即使是强效的 IFNγ 反应未能有效控制肺部感染部位的 Mtb。最近的研究表明， 肺，特别是肉芽肿，是一个免疫抑制环境，并且是最具保护性的 Mtb- 特定的 T 细胞被系统地排除在最需要它们的这些部位之外。 这种空间排斥的机制尚不完全清楚，免疫抑制细胞因子转化 生长因子 （TGF 正在成为结核病 T 细胞颠覆的有效因子。TGF 共定位 肉芽肿中含有 Mtb，表明 Mtb 可能直接激活 TGF 来颠覆这种微环境， 禁用 CD4 T 细胞功能，并消除 IFNα 信号传导 我们现在显示 Mtb 裂解物和培养物滤液。 蛋白质确实可以有效地从其惰性的潜在前体激活 TGFβ，这种活性是热不稳定的、分泌性的。 被 Mtb 抑制，并且被丝氨酸水解酶抑制剂抑制。在这里，我们将检验 Mtb 分泌 a 的假设。 丝氨酸蛋白酶毒力因子，直接处理和激活 TGF 以抑制生产性 CD4 T 细胞 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。