# Functional dynamics of TB granuloma architecture

> **NIH NIH U01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $616,269

## Abstract

Project Summary/Abstract
Understanding and eliminating TB depends on understanding the host and pathogen dynamics in granulomas,
where the outcomes of M. tuberculosis infection are determined. Despite substantial efforts, the cellular
composition, spatial interactions, and mechanisms that determine outcomes such as pathologic
granuloma necrosis are poorly understood. One explanation for the limited understanding of granulomas is that
most studies are performed in a single experimental system in isolation. We have formed a consortium to
perform and integrate studies of TB granulomas in three systems: humans, rhesus macaques, and new
strains of mice. In these three systems, we will address several major questions in TB granuloma biology:
what is the extent of diversity in cell composition in TB granulomas? What regulates cell trafficking and
spatial interactions in TB granulomas? What are the roles of type I interferons (TIIFN) and interferon
gamma (IFNg) in regulating and determining cell trafficking, differentiation, spatial relationships, and activation
states in TB granulomas? What are the pathogen and host determinants of necrosis, a pathologic outcome,
in TB granulomas? Our primary mode for investigating these and other questions will be high-parameter
multiplex immunostaining of TB granulomas from the three species, as this will provide essential insight into
the spatial relationships between immune cell subsets. Multiplex immunostaining will be complemented by
studies of live imaging of cell dynamics in rhesus macaque granulomas and by strategically-timed transfers
of labeled cells in rhesus macaques and diverse strains of mice. The value of the multiplex immunostaining
studies will be further enhanced by deep characterization of dissociated cell populations at the single-cell
level, using high parameter flow cytometry and single-cell transcriptomics. A uniquely important contribution
of our proposed project is the computational integration of data from humans, rhesus macaques, and new
strains of mice. By integrating multispecies data, we will identify the features of TB granulomas that are
common to all three species, and we will identify factors that are unique to granulomas in each species, to
guide further modifications to improve the utility of studies in animal models. Integration of the data from the
three species will allow studies in rhesus macaques to be compared with those of human samples and
new strains of mice; this will improve the understanding and interpretation of human pathology studies, and
enhance the value of studies that can take advantage of using the unique advantages of mice for mechanistic
studies. Together, our studies will advance the knowledge and understanding of TB biology, and guide
development of interventions to improve treatment outcomes, limit lung damage, and improve lung tissue
repair in people suffering from TB.

## Key facts

- **NIH application ID:** 10794293
- **Project number:** 5U01AI166309-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Joel D. Ernst
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $616,269
- **Award type:** 5
- **Project period:** 2022-03-18 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10794293

## Citation

> US National Institutes of Health, RePORTER application 10794293, Functional dynamics of TB granuloma architecture (5U01AI166309-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10794293. Licensed CC0.

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