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

• 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
• 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

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， 每年造成数百万人死亡。Mtb的多药耐药性导致治疗失败的风险更高 与死全球结核病的高负担要求发现新的细胞和分子生物学方法， 制定有效的保护战略。已知粘膜相关不变T（MAIT） 细胞对非肽类细菌代谢产物产生应答，并作为先天性的类似传感器发挥作用， 对结核病感染的反应。Mtb感染中MAIT细胞的激活需要Mtb代谢产物的识别 由单态性抗原呈递分子以不受个体限制的方式呈递的抗原，类似于 病原体相关分子模式与先天受体的结合。预期活化的MAIT细胞 在早期或慢性结核病感染时诱导快速抗Mtb MAIT细胞应答。虽然最近的研究 提供了强有力的证据支持MAIT细胞在小鼠和人类中对结核病的保护作用， E.大肠杆菌在小鼠和灵长类动物中诱导了部分保护作用， 其他灵长类动物这种由大肠杆菌抗原诱导的针对Mtb的次优保护性MAIT细胞应答 感染可能是因为Mtb提供了不同的抗原来激活和识别MAIT细胞， E.大肠杆菌复合物。事实上，MAIT细胞对各种病原体的反应不同，而目前的MAIT细胞对病原体的反应不同。 关键的未知因素是哪种Mtb抗原刺激抗Mtb MAIT细胞应答。根据我们经过验证的 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央 假设Mtb代谢物刺激人MAIT细胞对Mtb感染应答有两个目的。在 目的1，我们将使用我们的纯化和初步鉴定的Mtb激动剂诱导保护性抗Mtb应答 与E. coli抗原。MTB激动剂会刺激 来自健康供体、结核病患者和肺组织的MAIT细胞。MAIT细胞反应的保护 将主要通过杀死Mtb感染的细胞和抑制Mtb生长来测量。在目标2中，我们将确定 使用功能代谢组学研究Mtb激动剂的化学结构以刺激抗Mtb MAIT细胞应答。 我们已经获得了MAIT刺激馏分使用高压液相色谱法和鉴定 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 从活性化学级分进一步确定Mtb激动剂的结构。产生新型结核分枝杆菌代谢物 将被化学合成或纯化用于MAIT细胞活化和针对Mtb感染的保护。 在成功完成后，我们将阐明结核分枝杆菌代谢产物的结构和功能，以诱导一个新的结核分枝杆菌代谢产物。 保护MAIT细胞对抗结核感染。最终，Mtb抗原可以应用于 了解MAIT在结核病中的激活机制，并开发新的抗分枝杆菌药物 抗击人类结核病的战略。