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, PPAR?, 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 PPAR?, 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 PPAR? receptors, and the vitamin A converting enzyme RALDH, alongside ligand agonists, all-trans retinoic acid (RAR), 9-cis retinoic acid (RXR), and thiazolidenones (PPAR?). 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 PPAR? signaling on TB immunity. Guinea pigs with sufficient or severely deficient vitamin A status will be treated with or without rosiglitazone, a specific PPAR? 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 results will guide development of new host-directed therapies to minimize risk and improve outcome of exposure in TB-endemic regions.

Public Health Relevance

Vitamin A deficiency is a widespread problem in low-income countries and recently has been identified as a strong risk factor for developing clinical tuberculosis. This research aims to better understand the mechanisms by which a lack of vitamin A influences the ability of immune cells to respond to infection, and consequently, the outcome of tuberculosis disease. The goal will be to develop new host-directed therapies that prevent disease progression or improve response to standard antibiotic treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI144662-02
Application #
9894731
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Eichelberg, Katrin
Project Start
2019-03-15
Project End
2021-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Microbiology/Immun/Virology
Type
Schools of Veterinary Medicine
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523