# Modulation of immunity to tuberculosis through vitamin A-dependent nuclear receptors

> **NIH NIH R21** · COLORADO STATE UNIVERSITY · 2020 · $228,000

## Abstract

Project Summary
Tuberculosis (TB), the leading cause of death due to an infectious disease, is faced by a number of challenges,
one of which is our inability to predict disease outcome after exposure. The limited knowledge on risk factors for
TB progression and the mechanisms by which these promote susceptibility limits the ability to develop new
prevention and treatment approaches. Recently, our collaborators have identified moderate, subclinical vitamin
A deficiency as a substantial risk factor for developing active TB, carrying a 10-fold higher risk. The substantial
TB risk carried by deficiency in vitamin A highlights the need to understand the mechanisms by which this
molecule contributes to protection, particularly in the context of malnutrition among TB-affected communities.
Vitamin A functions through nuclear receptors, which are ligand-activated transcription factors. Other nuclear
receptors beyond vitamin A receptors have been shown to regulate immune function and contribute to response
to M. tuberculosis infection. In particular, PPARγ, a nuclear receptor with obligatory association with vitamin A
receptors is enriched in macrophages and influences the immune response during TB. Because we have shown
that rosiglitazone, an activator of PPARγ, improves outcome of tuberculosis in guinea pigs, we hypothesize that
that availability of vitamin A and PPAR ligands together influence the transcriptional outcome during TB and
consequently, the ability to control infection. The goal of this research is to better understand the contribution of
nuclear receptor-ligand interaction, and the impact of impaired vitamin A availability on immune response, control
of bacterial growth, and TB disease outcome. These will be investigated through Aims using bone marrow-
derived macrophage cell models and a guinea pig model of vitamin A deficiency, both developed in our
laboratory. We will first determine the contribution of ligand activation of nuclear receptor heterodimers to
transcriptional and microbicidal response to infection with M. tuberculosis in bone marrow macrophages. This
approach uses a combination of validated knock-down techniques targeting vitamin A (RAR, RXR) and PPARγ
receptors, and the vitamin A converting enzyme RALDH, alongside ligand agonists, all-trans retinoic acid (RAR),
9-cis retinoic acid (RXR), and thiazolidenones (PPARγ). This will be followed by the use of our recently developed
guinea pig model of dietary vitamin A deficiency to determine the impact of vitamin A and PPARγ signaling on
TB immunity. Guinea pigs with sufficient or severely deficient vitamin A status will be treated with or without
rosiglitazone, a specific PPARγ agonist, based on our previous assessment of this drug in guinea pigs and
immune response and disease outcome measured. Upon completing these experiments, we will have
determined the impact of vitamin A and nuclear receptor control over response to infection and consequently,
TB disease outcome. These resu...

## Key facts

- **NIH application ID:** 9894731
- **Project number:** 5R21AI144662-02
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Brendan Podell
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $228,000
- **Award type:** 5
- **Project period:** 2019-03-15 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9894731

## Citation

> US National Institutes of Health, RePORTER application 9894731, Modulation of immunity to tuberculosis through vitamin A-dependent nuclear receptors (5R21AI144662-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9894731. Licensed CC0.

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