Friday, March 21, 2025
3/21/2025
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.
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