# Molecular Analysis of Host Immune Response in Leprosy

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $803,706

## Abstract

PROJECT SUMMARY / ABSTRACT
T cells are required for protection against intracellular infections such as leprosy and tuberculosis; however,
the specific mechanisms by which they contribute to host immunity remain unresolved. Leprosy, caused by the
intracellular pathogen Mycobacterium leprae (mLEP), provides an accessible model to investigate human
immune responses to intracellular bacterial infection. The spectrum of clinical manifestations of leprosy
correlates with the immune response to mLEP. Patients with tuberculoid leprosy (T-lep) develop protective
immunity and eliminate the infection, whereas those with lepromatous leprosy (L-lep) sustain a progressive
infection. The dynamics of T cell immunity can be studied in the context of the reversal reaction (RR), in which
patients upgrade from L-lep to T-lep. We established that in patients with leprosy, T cell subsets differ
dramatically between the blood and lesions, indicating the importance of studying the immune response at the
site of disease. During the first 38 years of this R01, we discovered new mechanisms by which CD4+ and CD8+
T cells engender antimicrobial activity against mLEP in infected human macrophages (MØs), which we also
showed to be relevant in Mycobacterium tuberculosis infection. These include 1) cytolytic T lymphocyte release
of the antimicrobial protein granulysin; 2) Th1 cell secretion of IFN- which activates vitamin D-dependent
induction of the antimicrobial proteins cathelicidin and DEFB4 in MØs; and 3) Th17 cell release of the
antimicrobial protein IL-26, which enters myeloid cells targeting intracellular bacteria. None of these
mechanisms exist in mice, necessitating the study of human disease. By integrating scRNA-seq and spatial
transcriptomics, we identified an ecosystem of T cells, MØs, keratinocytes, fibroblasts, and endothelial cells
that together express 66 genes involved in the antimicrobial response in leprosy. We also discovered that
TREM2 MØs are a major MØ subpopulation in the disseminated L-lep form of leprosy, representing the mLEP-
infected foamy MØs that are unable to eliminate the pathogen. We hypothesize that T cell-dependent
antimicrobial mechanisms can overcome immune suppression in TREM2 MØs and thus eliminate mLEP. Our
specific aims are to: Aim 1: Elucidate the mechanisms by which T cells mediate an antimicrobial response to
intracellular mycobacteria, Aim 2: Define mechanisms by which TREM2 MØs contribute to the pathogenesis of
progressive infection in leprosy; and, Aim 3: Identify immune pathways that can augment antimicrobial
responses in leprosy, including in CD8+ T cells and TREM2 MØs. The proposed studies will provide insights
into the mechanisms of pathogenesis and host defense in intracellular bacterial infections.

## Key facts

- **NIH application ID:** 10878573
- **Project number:** 2R01AI022553-40
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** ROBERT L MODLIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $803,706
- **Award type:** 2
- **Project period:** 1991-01-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878573

## Citation

> US National Institutes of Health, RePORTER application 10878573, Molecular Analysis of Host Immune Response in Leprosy (2R01AI022553-40). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10878573. Licensed CC0.

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