# Molecular Analysis of Host Immune Response in Leprosy

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $666,666

## Abstract

PROJECT SUMMARY / ABSTRACT
The mechanisms by which T cells contribute to host immunity against intracellular infections, as in leprosy and
tuberculosis, remain unclear. Leprosy, caused by the intracellular pathogen Mycobacterium leprae (mLEP),
predominantly localized to skin, represents an accessible model to investigate human immune responses to
intracellular bacterial infection. The clinical manifestations of leprosy form a spectrum, which correlates with the
immune response to the pathogen. Patients with tuberculoid leprosy (T-lep) develop protective immunity to wall
off and eliminate the infection, whereas those with lepromatous leprosy (L-lep) sustain a disseminated and
progressive infection. This proposal is based upon the premise that traditional human Th1 T cells are not
sufficient for protection against mycobacterial disease and that characterization of molecular mechanisms and
markers of other antimicrobial T cell populations may lead to unique biomarkers of protective immunity,
critically needed to develop protective vaccines. Our preliminary data identify two novel antimicrobial T-cell
subpopulations, both bearing innate receptors that contribute to protective immunity against intracellular
mycobacteria, and directly or indirectly capable of reducing viability of mLEP and other pathogens. First, a
subpopulation of CD8+ cytolytic T lymphocytes (CTLs) that express a specific NK receptor can be triggered by
that innate receptor to release the anti-mycobacterial protein granulysin (GNLY). Second, a subpopulation of
CD4+ Th17 cells that express IL-1RI can be triggered by IL-1β to secrete the antimicrobial protein IL-26.
Notably, neither GNLY nor IL-26 exists in mice. We hypothesize that innate receptors on human CD4+ and
CD8+ T-cell subpopulations, in addition to T cell receptors (TCRs), can be directly activated to induce the
release antimicrobial effector molecules that contribute to host defense against intracellular pathogens. We
propose to identify molecular markers of CD4+ and CD8+ antimicrobial T-cell subpopulations, facilitating
investigation of the mechanisms by which those cells are induced, activated and able to reduce the viability of
intracellular pathogens. Our specific aims are to: 1) Elucidate mechanisms by which CD8+ CTLs are triggered
via innate receptors to mediate an antimicrobial response, 2) Define mechanisms by which CD4+ Th17 cells
mediate antimicrobial activity, and 3) Identify the innate pathways that induce antimicrobial T-cell differentiation
in leprosy. The identification of antimicrobial T cell mechanisms and potential functional biomarkers will
facilitate new strategies for monitoring protective responses, evaluating new vaccine candidates and
therapeutic interventions against diseases caused by intracellular bacteria.

## Key facts

- **NIH application ID:** 10654746
- **Project number:** 5R01AI022553-39
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** ROBERT L MODLIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $666,666
- **Award type:** 5
- **Project period:** 1991-01-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10654746

## Citation

> US National Institutes of Health, RePORTER application 10654746, Molecular Analysis of Host Immune Response in Leprosy (5R01AI022553-39). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10654746. Licensed CC0.

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