# Epigenetic Study of Resistance to Infection by Mycobacterium tuberculosis

> **NIH NIH R21** · EMORY UNIVERSITY · 2022 · $195,625

## Abstract

PROJECT SUMMARY/ABSTRACT
 Although tuberculosis (TB) has been curable and preventable for decades, TB remains a major public
health threat globally, with one-quarter of the world's population currently infected. Although efforts to control
TB have primarily focused on treating active TB cases, greater emphasis on preventing new infections will be
needed to achieve the EndTB goal of fewer than 10 TB cases per 100,000 population by 2035. However, the
development of biomedical interventions to prevent TB infection, such as a TB vaccine, has been hampered by
a lack of understanding of host factors that mediate susceptibility and resistance to Mycobacterium
tuberculosis (Mtb) infection following exposure.
 A genetic basis for resistance to Mtb infection has long been postulated. Gene expression can also be
influenced by epigenetic modifications, such as DNA methylation, which can mediate inherited, behavioral and
co-morbid effects (e.g., smoking, aging, diabetes), and influence immunological function. Thus, epigenetics
may play a pivotal role in a variety of diseases, particularly infectious diseases. However, no study has been
conducted to understand the impact of epigenetic modifications on resistance to Mtb infection at a population
level. In the proposed R21, we will conduct a hypothesis-generating, epigenome-wide study of >850,000 DNA
methylation sites to identify epigenetic predictors of resistance among household contacts who remain
uninfected, despite well-characterized exposure to active TB. We will leverage our recently funded NIH R01
study of 4,000 household contacts (R01AI139406, MPI Gandhi/Sun). In this parent R01 study, we are
identifying individuals with resistance to Mtb infection and conducting GWAS and metabolomic analysis to
characterize factors associated with resistance. The proposed R21 will utilize clinical and exposure data and
DNA specimens from participants enrolled in the parent R01 study, making this epigenetic study highly
feasible. In Aim 1, we will conduct agnostic searches for epigenomic associations, in addition to targeted
analyses of candidate genes. In Aim 2, we will combine GWAS data from the parent R01 and DNA methylation
sites identified in Aim 1 to elucidate the causal relationships between epigenetic and resistance using
Mendelian Randomization.
 The findings of this R21 would provide preliminary data to facilitate a future, definitive investigation of
epigenetics and resistance to Mtb infection. A greater understanding of epigenetics in Mtb infection will provide
insights for vaccine development and other novel biomedical interventions to prevent Mtb infection.

## Key facts

- **NIH application ID:** 10424387
- **Project number:** 5R21AI152031-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Neel Rajnikant Gandhi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $195,625
- **Award type:** 5
- **Project period:** 2021-06-08 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10424387

## Citation

> US National Institutes of Health, RePORTER application 10424387, Epigenetic Study of Resistance to Infection by Mycobacterium tuberculosis (5R21AI152031-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10424387. Licensed CC0.

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