# Hypoxia,  tuberculosis, and T cell dysfunction

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $805,368

## Abstract

Abstract. After Mycobacterium tuberculosis (Mtb) infection, 5-10% of people develop clinically evident
tuberculosis (TB), most within two years. This leads to 10 million new cases of TB and 1.5 million deaths each
year. Why immunity fails and permits recrudescence in people that initially control Mtb is unknown. Risk factors
include diabetes, malnutrition, alcoholism, cancer, and smoking, all which cause metabolic stress. Our long-term
goal is to understand the drivers of immune failure and identify protective mechanisms of immunity. A major
knowledge gap is how various metabolic insults affect cellular immunity in the infected lung. Our over-arching
hypothesis is that that during TB, metabolic stressors such as granuloma hypoxia contribute to T cell dysfunction,
degrade immunity, and impair Mtb containment. We and others find that T cells from patients with pulmonary TB
and chronically Mtb-infected mice are dysfunctional. Dysfunctional CD8 T cells (e.g., exhausted CD8 T cells)
have been intensively studied because of their role in tumor immunity. In contrast, far less is known about CD4
T cell dysfunction. We will investigate both CD4 and CD8 T cells and focus on CD4 T cells as they are crucial
for immunity to Mtb. We will use the murine TB model to investigate how metabolic stress affects T cell function
and contributes to TB pathogenesis. An important component of our strategy is to compare T cells from
susceptible mice that develop hypoxic granulomas with T cells from resistant mouse strains. The first aim is to
“Determine the relationship between metabolic perturbation and T cell dysfunction.” A high-resolution map of T
cell responses to Mtb in susceptible and resistant mice will be assembled after performing scRNASeq, TCRseq,
conventional flow cytometry and MetFlow (to assess cell metabolism). We will determine whether dysfunctional
T cells differ in their control of Mtb in vitro and in vivo. Secondly, we will “Determine how hypoxia affects T cell
immunity against Mtb.” Using hypoxia fate reporter mice, we will study how hypoxia affects T cell function in vivo.
These studies will be coupled with mechanistic studies using hypoxic culture conditions in vitro. We will establish
how hypoxia, metabolic stress, and T cell function are related, and whether hypoxia is detrimental to protective
T cell responses during TB. Finally, Aim 3 will “Assess how metabolic interventions alter T cell function and TB
outcome.” We predict that drugs that correct underlying metabolic perturbations can improve T cell function and
enhance control of Mtb infection. Using the hypoxic mouse models, proof-of-principle experiments will be done
to determine how drugs that affect neovascularization, target metabolism, or protect mitochondria, affect Mtb
containment in vivo. Our studies will determine how hypoxia and metabolic stress affect immunity to Mtb and
provide insight into why CD4 immunity fails. As T cells are essential in containing Mtb infection, we hypothesize
...

## Key facts

- **NIH application ID:** 10850797
- **Project number:** 5R01AI172905-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** SAMUEL M BEHAR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $805,368
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10850797

## Citation

> US National Institutes of Health, RePORTER application 10850797, Hypoxia,  tuberculosis, and T cell dysfunction (5R01AI172905-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10850797. Licensed CC0.

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