# Dynamics of the cellular and molecular architecture of human pulmonary TB granulomas

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $647,775

## Abstract

PROJECT SUMMARY/ABSTRACT
Immunologically, the enigma of the granuloma is best reflected in that sterile, bacillus-controlling, and
progressive granulomas can coexist in the same lung, with the progressive form ultimately killing the host. This
observation is consistent with the modern concept of “concomitant immunity: the paradoxical immune status in
which resistance to reinfection coincides with the persistence of the original infection”. Here, we will test the
hypothesis that the development of concomitant immunity regulates macrophage differentiation, influencing
granuloma formation and ultimately the outcome of the battle between the immune response and the pathogen
Mycobacterium tuberculosis. To do so, we will use single cell RNA sequencing and spatial sequencing to map
the coordinates of cell populations and antimicrobial mediators in human TB granulomas. We propose the
following specific aims: 1) elucidate the cellular and molecular architecture of human pulmonary TB
granulomas, 2) investigate the role of macrophage subpopulations that contribute to the antimicrobial response
vs. pathogenesis of TB granulomas; and 3) investigate the role of T cell subpopulations in contributing to
concomitant immunity in TB granulomas. We will identify specific cell subpopulations that contribute to host
defense by comparing individual TB granulomas with varying bacterial loads and those with pathogenesis by
examining the dynamic change with the progression of primary lesions, to early lesions with bronchial
obstruction, to post-primary granulomas. We will determine the role of macrophage subpopulations in host
defense and pathogenesis, in particular the foamy macrophages that we discovered express TREM2. We will
investigate which T cell populations are predictors of individuals that respond to chemotherapy versus those
that are resistant and therefore serve as biomarkers. These studies will bring together collaborators at UCLA,
the Ragon Institute and the Institut Pasteur de Tunis with expertise in clinical tuberculosis, immunology and
molecular biology to gain new insight into the mechanisms by which concomitant immunity influences
granuloma structure to optimize host defense against TB.

## Key facts

- **NIH application ID:** 10569668
- **Project number:** 5R01AI166313-02
- **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:** $647,775
- **Award type:** 5
- **Project period:** 2022-02-10 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10569668

## Citation

> US National Institutes of Health, RePORTER application 10569668, Dynamics of the cellular and molecular architecture of human pulmonary TB granulomas (5R01AI166313-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10569668. Licensed CC0.

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