# Identification of Mycobacterium tuberculosis-derived metabolites acting as ligands for MR1-restricted T cells.

> **NIH NIH R21** · STATE UNIVERSITY NEW YORK STONY BROOK · 2024 · $206,200

## Abstract

Project Summary
Tuberculosis (TB) remains a leading global cause of morbidity and mortality, yet the immune
correlates of protection remain elusive. Improved understanding of the initial immune events
following Mycobacterium tuberculosis (Mtb) exposure that determine progression to infection and
active disease is a critical priority for developing novel immune therapies and vaccines. Our
laboratory studies innate lymphocyte biology and utilizes systems immunology approaches to
identify targets for immune therapies against TB. In this proposal, we will focus on one of the
most abundant innate lymphocytes responding to Mtb, mucosal-associated invariant T (MAIT)
cells, that recognize activating/inhibitory microbial metabolites of riboflavin metabolism that act as
non-peptide antigens presented by the evolutionarily conserved MHC I-related protein, MR1.
While MAIT cells are activated by Mtb in vitro and in vivo, they do not robustly expand after
infection. Moreover, MAIT cells are depleted during chronic murine and human TB disease. Our
working hypothesis to explain this observation is that Mtb synthesizes an abundance of inhibitory
MR1 ligands, which suppress MAIT cell activity and contribute to immune evasion. We have
recently developed LC-MS technologies to detect MR1 ligands within biological samples and will
couple this platform with our expertise in in mycobacterial genetics and TB immunology to define
the MR1 metabolome of Mtb as compared to non-mycobacterial species as well as Mtb riboflavin
auxotrophs we will generate by inducible CRISPRi knockdown to transiently perturb specific
branchpoints of mycobacterial riboflavin biosynthesis. In parallel, we will quantify Mtb-specific
MR1 ligands and MR1 expression/MAIT cell function in vivo during initial Mtb exposure and
infection in humans who have been recently exposed to Mtb in their household. In sum, our
approach will identify MR1 ligands specific to Mtb metabolism and determine their impact on
MR1/MAIT cell activity, informing future targeting of Mtb Vitamin B metabolism in TB immune
therapies and mucosal vaccines.

## Key facts

- **NIH application ID:** 10820506
- **Project number:** 5R21AI171578-02
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Charles Kyriakos Vorkas
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $206,200
- **Award type:** 5
- **Project period:** 2023-04-04 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10820506

## Citation

> US National Institutes of Health, RePORTER application 10820506, Identification of Mycobacterium tuberculosis-derived metabolites acting as ligands for MR1-restricted T cells. (5R21AI171578-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10820506. Licensed CC0.

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