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

> **NIH NIH R01** · TEXAS BIOMEDICAL RESEARCH INSTITUTE · 2024 · $648,933

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10849771
- **Project number:** 7R01AI173245-02
- **Recipient organization:** TEXAS BIOMEDICAL RESEARCH INSTITUTE
- **Principal Investigator:** Shouxiong Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $648,933
- **Award type:** 7
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10849771

## Citation

> US National Institutes of Health, RePORTER application 10849771, M. tuberculosis metabolites to activate human mucosal-associated invariant T cells (7R01AI173245-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10849771. Licensed CC0.

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