# The role of CD38 in immunity to tuberculosis

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $209,375

## Abstract

Abstract. The WHO estimates that 25% of the world’s population has been infected with Mycobacterium
tuberculosis (Mtb), the bacterium that causes the disease tuberculosis (TB). Despite major advances in the
field, how T cells and macrophages collaborate to control intracellular infection is incompletely defined.
Alveolar macrophages are the first cell that Mtb infects but ultimately, CD11c+ monocyte-derived macrophages
(MDM) become the major infected cell type. Our studies show that Mtb-infected CD11c+ MDM cells can be
distinguished from uninfected bystander macrophages by their expression of cell surface CD38, CD14,
ABCA1. CD38 is also expressed by activated T cells. Peripheral blood and lung CD4 T cells from people with
TB also express CD38, which has been proposed as a biomarker to distinguish active TB from latent TB, and
to monitor treatment. While these data establish CD38 as an interesting cellular marker, its known biological
functions suggested that it could have an important role in immunity to TB. CD38 is a multifunctional
ectoenzyme that converts NAD+ to NAADP or cADPR. These second messengers trigger intracellular Ca2+
release, which promotes phagocytosis and phagolysosome formation in macrophages. Our preliminary studies
show that CD38 knockout (CD38KO) mice have higher Mtb burdens in the lung and significantly reduced
survival, compared to CD38-sufficient mice. How CD38 promotes resistance to Mtb is unknown. This proposal
will identify the cellular and molecular mechanism(s) by which CD38 contributes to protection against Mtb. We
propose three aims: 1) Determine the cellular basis for how CD38 contributes to anti-Mtb immunity in vivo; 2)
Investigate how CD38 affects intracellular survival of Mtb within macrophages; and 3) Assess how CD38
signaling affects control of intracellular Mtb in human macrophages. Our goal is to define the basic cellular and
molecular mechanisms by which CD38 promotes antimycobacterial immunity. We suggest that CD38 converts
T cell signals into a macrophage antibacterial defense program. Our proposed in vivo studies using the murine
TB model, and in vitro studies using murine and human macrophages, will establish how CD38 functions to
enhance immunity to TB and provide a strong foundation for further investigations. As well-defined agonists
and antagonists exist for CD38, and it is already a therapeutic target for other diseases, an improved
understanding of how CD38 modulates immunity against Mtb infection could identify it as a novel HDT target
for TB and other infectious diseases.

## Key facts

- **NIH application ID:** 10876315
- **Project number:** 5R21AI178473-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** SAMUEL M BEHAR
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $209,375
- **Award type:** 5
- **Project period:** 2023-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10876315

## Citation

> US National Institutes of Health, RePORTER application 10876315, The role of CD38 in immunity to tuberculosis (5R21AI178473-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10876315. Licensed CC0.

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