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.

项目摘要 结核分枝杆菌（MTB）通过分泌一系列调节病毒因素来促进其生存 免疫。结果，对结核病的免疫力（TB）更难实现，无论是 疫苗接种或自然感染。从结核病保护的一个明确相关的是有效的CD4 T细胞响应 这导致了干扰素伽玛的产生（IFN。但是，一个长期存在的问题是为什么即使是强大的 IFN反应无法有效控制肺部感染部位的MTB。最近的工作表明 肺，尤其是肉芽肿，是一种免疫抑制环境，是最受保护的MTB- 特定的T细胞被系统地排除在最需要的地方。而 该空间排除的机制尚不完全了解，免疫抑制细胞因子转化 生长因子（TGF作为TB中T细胞颠覆的潜在因素出现。TGF强烈共定位 粒状瘤中的MTB，表明MTB可能会直接激活TGF来颠覆这种微环境， 禁用CD4 T细胞功能，并熄灭IFN信号。我们现在表明MTB裂解物和培养过滤器 蛋白质确实可以从其惰性潜在前体中有效激活TGF。这项活动是热量的，分泌的 由MTB，并被丝氨酸水解酶抑制剂抑制。在这里，我们将测试MTB分泌的假设 串行蛋白质病毒因子直接处理和激活TGF抑制生产性CD4 T细胞 MTB感染部位的激活。该项目旨在确定一种新的直接主持人互动 MTB发病机理的机制是免疫系统无法控制MTB感染的基础。