# Glutamine metabolism in tuberculosis

> **NIH NIH R21** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2022 · $237,704

## Abstract

Abstract
Mycobacterium tuberculosis (Mtb) remains the most successful human pathogen, causing 1.5 million deaths in
2018. Accumulating evidence suggests that Mtb’s ability to survive, persist and cause disease is largely due to
its ability to subvert the host immune and antimicrobial response to infection. Recent advances in
immunometabolism studies have shown that a metabolic shift to glycolysis, aka the Warburg effect, is critical for
the activation and effector functions of immune cells to control the infection. However, there are limited studies
on how the change of metabolic state of infected macrophages affects the activation and function of innate and
adaptive immunity in TB. Our laboratory and others have characterized the immunometabolic changes in multiple
model of TB and found that the metabolic remodeling to the HIF-1-mediated Warburg effect is a general response
to Mtb infection. Through detailed analysis of immunometabolic properties of Mtb-infected macrophages using
transcriptomics, metabolomics and therapeutic compound treatment, we discovered novel evidence that M1
polarization at initial stage of macrophage infection is accompanied by increased glutamine uptake and
metabolism. Given the pleiotropic roles of glutamine metabolism, including anaplerotic reactions from the TCA
cycle, redox homeostasis, and synthesis of nucleotides and NADPH, findings from our studies suggest that
glutamine uptake and metabolism constitute an integral component of metabolic remodeling program of M1
macrophages. Based on these observations, we hypothesize that glutamine functions as important carbon and
nitrogen source for immune cells and that its availability and metabolism are essential for the activation and
function of host innate and adaptive immunity against Mtb infection. To test our hypothesis, we propose two
Specific Aims. In Aim 1, we will define the role of glutamine in mediating the metabolism and physiology of M1
macrophages. We will also decipher the metabolic footprints of glutamine as carbon and nitrogen source during
M1 polarization using stable isotope tracing metabolomics with 13C (1-13C and 5-13C) glutamine and 15N (a-N,
and g-N) glutamine. In Aim 2, we will characterize the role of glutamine metabolism in mediating the activation
and functions of innate and adaptive immune cells using therapeutically validated small molecule inhibitor for
glutaminolysis pathway. We will also evaluate whether supplementation of glutamine to Mtb-infected animals
can serve as a viable strategy of adjunct host directed therapies (HDTs) to boost antimicrobial response of host
immune cells against Mtb infection in a mouse model of TB. By elucidating the effects of glutamine metabolism
on the functional property of host immune cells, this study will establish a novel immunometabolic aspect of TB
research. Outcomes of this study will open new avenues for the development of new adjunct HDTs by targeting
glutamine metabolism to treat TB worldwide.

## Key facts

- **NIH application ID:** 10445338
- **Project number:** 5R21AI163824-02
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Lanbo Shi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $237,704
- **Award type:** 5
- **Project period:** 2021-07-06 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445338

## Citation

> US National Institutes of Health, RePORTER application 10445338, Glutamine metabolism in tuberculosis (5R21AI163824-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10445338. Licensed CC0.

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