M. tuberculosis metabolites to activate human mucosal-associated invariant T cells

结核分枝杆菌代谢物可激活人粘膜相关的不变 T 细胞

基本信息

批准号：
10737315
负责人：
Shouxiong Huang
金额：
$ 55.93万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737315
关键词：
Agonist Antibiotic Therapy Antigen Presentation Antigens Antimycobacterial Agents Bacterial Antigens Bacterial Infections Binding Biological Assay Biology Blood Cells Cessation of life Chemical Structure Chemicals Chronic Clonal Expansion Complex Data Dipeptidyl-Peptidase IV Discrimination Disease Drug resistant Mycobacteria Tuberculosis Elements Escherichia coli Future Growth Health High Pressure Liquid Chromatography Hour Human Immune response In Vitro Individual Infection Inflammation Inflammatory Introns Ligands Mass Spectrum Analysis Measures Mediastinal lymph node group Modeling Molecular Molecular Target Mucous Membrane Multi-Drug Resistance Mus Mycobacterium tuberculosis Mycobacterium tuberculosis antigens Nature Outcome Patients Pattern Peptides Population Predisposition Primates Proteins Risk Role Single Nucleotide Polymorphism Structure Structure of parenchyma of lung T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Therapeutic Effect Tissues Toxic effect Tuberculosis analog antigen binding candidate identification cellular targeting chemical synthesis cytokine design fighting global health high risk human monoclonal antibodies in vivo metabolomics non-tuberculous mycobacterial infection novel pathogen prevent programs public health relevance receptor response sensor side effect transcriptomics

项目摘要

Mycobacterium tuberculosis (Mtb) infects over a quarter of the global population and remains a significant health threat causing millions of deaths annually. Multidrug resistance of Mtb leads to a higher risk of failed treatment and death. This high tuberculosis burden worldwide demands the discovery of novel cellular and molecular targets for developing efficacious protective strategies. It is known that mucosal-associated invariant T (MAIT) cells respond to non-peptidic bacterial metabolites and function as innate-like sensors to elicit rapid immune responses against Mtb infections. MAIT cell activation in Mtb infection requires the recognition of Mtb metabolite antigens presented by a monomorphic antigen-presenting molecule in an individual-unrestricted manner, similar to the binding of pathogen-associated molecular patterns to innate receptors. Activated MAIT cells are expected to induce rapid anti-Mtb MAIT cell responses at early or chronic tuberculosis infections. Although recent studies provided strong evidence supporting the protective role of MAIT cells against tuberculosis in mice and humans, the model antigen from E. coli induced partial protection in mice and primates, together with side effects in some other primate subjects. This suboptimal protective MAIT cell response induced by the E.coli antigen against Mtb infection is likely because Mtb provides different antigens to activate and recognize MAIT cells or the potential toxic effect of the E. coli compound. Indeed, MAIT cells respond differently to various pathogens, and the current critical unknown is which Mtb antigens stimulate anti-Mtb MAIT cell responses. Based on our validated functional metabolomics platform, we will apply these chemical biology approaches to test the central hypothesis that Mtb metabolites stimulate human MAIT cell response against Mtb infections with two aims. In Aim 1, we will use our purified and preliminarily identified Mtb agonists to induce protective anti-Mtb responses of polyclonal and monoclonal human MAIT cells in comparison with the E. coli antigen. Mtb agonists will stimulate MAIT cells from healthy donors, tuberculosis patients, and lung tissues. The protection of MAIT cell responses will be mainly measured by killing Mtb-infected cells and inhibiting Mtb growth. In Aim 2, we will determine the chemical structures of Mtb agonists using functional metabolomics to stimulate anti-Mtb MAIT cell responses. We have obtained MAIT-stimulatory fractions using high-pressure liquid chromatography and identified candidate Mtb agonists that activated MAIT cells. Our mass spectrometry-based functional metabolomics will further define the structures of Mtb agonists from active chemical fractions. Resulted in novel Mtb metabolites will be either chemically synthesized or purified for MAIT cell activation and protection against Mtb infections. Upon successful completion, we will elucidate the structures and functions of Mtb metabolites to induce a protective MAIT cell response against tuberculosis infections. Ultimately, Mtb antigens can be applied to understand MAIT activation mechanisms in tuberculosis disease and develop novel anti-mycobacterial strategies for fighting tuberculosis in humans.

结核分枝杆菌 (Mtb) 感染了全球四分之一以上的人口，并且仍然是一个重要的健康问题每年造成数百万人死亡的威胁。结核分枝杆菌的多重耐药性导致治疗失败的风险更高和死亡。全球范围内的高结核病负担需要发现新的细胞和分子治疗方法制定有效保护策略的目标。众所周知，粘膜相关不变 T (MAIT) 细胞对非肽细菌代谢物做出反应，并发挥类似先天传感器的作用，引发快速免疫针对 Mtb 感染的反应。 Mtb 感染中的 MAIT 细胞激活需要识别 Mtb 代谢物由单态抗原呈递分子以个体不受限制的方式呈递的抗原，类似病原体相关分子模式与先天受体的结合。预计 MAIT 细胞会被激活在早期或慢性结核感染时诱导快速抗 Mtb MAIT 细胞反应。尽管最近的研究提供了强有力的证据支持 MAIT 细胞对小鼠和人类结核病的保护作用，来自大肠杆菌的模型抗原在小鼠和灵长类动物中诱导了部分保护，同时在某些动物中产生了副作用其他灵长类动物。由大肠杆菌抗原诱导的针对 Mtb 的次优保护性 MAIT 细胞反应感染可能是因为 Mtb 提供不同的抗原来激活和识别 MAIT 细胞或潜在的大肠杆菌化合物的毒性作用。事实上，MAIT 细胞对各种病原体的反应不同，目前的关键未知的是哪种 Mtb 抗原会刺激抗 Mtb MAIT 细胞反应。根据我们验证的功能代谢组学平台，我们将应用这些化学生物学方法来测试中心假设 Mtb 代谢物刺激人类 MAIT 细胞针对 Mtb 感染的反应，有两个目的。在目标 1，我们将使用纯化和初步鉴定的 Mtb 激动剂来诱导保护性抗 Mtb 反应多克隆和单克隆人 MAIT 细胞与大肠杆菌抗原的比较。 Mtb激动剂会刺激 MAIT 细胞来自健康捐献者、结核病患者和肺组织。 MAIT 细胞反应的保护主要通过杀死Mtb感染的细胞并抑制Mtb生长来测量。在目标 2 中，我们将确定使用功能代谢组学刺激抗 Mtb MAIT 细胞反应的 Mtb 激动剂的化学结构。我们使用高压液相色谱法获得了 MAIT 刺激组分，并鉴定了激活 MAIT 细胞的候选 Mtb 激动剂。我们基于质谱的功能代谢组学将进一步确定活性化学组分中 Mtb 激动剂的结构。产生新的 Mtb 代谢物将通过化学合成或纯化来激活 MAIT 细胞并防止 Mtb 感染。成功完成后，我们将阐明 Mtb 代谢物的结构和功能，以诱导 MAIT 细胞对结核感染的保护性反应。最终，Mtb 抗原可应用于了解结核病中的 MAIT 激活机制并开发新型抗分枝杆菌药物对抗人类结核病的策略。