# Characterization of Genomics and Metabolomics among Individuals Highly-Exposed, but resistant to Mtb Infection

> **NIH NIH R01** · EMORY UNIVERSITY · 2021 · $775,211

## Abstract

Although tuberculosis (TB) has been curable and preventable for nearly 75 years, TB remains a major public
health threat globally, as the world’s leading infectious disease cause of death. Goals to “eliminate” TB by 2035
are unlikely to be achieved in this century with the currently available control strategies. Development of new
therapeutic and prevention tools, such as a TB vaccine, is needed, but such efforts are hampered by
insufficient understanding of the mechanisms of protection against Mycobacterium tuberculosis (Mtb) infection.
Although a host genetic role in protection has long been postulated and family-based linkage studies have had
promising results, no specific genes have yet been carefully characterized. Research efforts to date have been
limited by challenges in defining clinical phenotypes of Mtb resistance, small sample sizes, and difficulty in
measuring the degree of exposure to Mtb. With recent advances in high-throughput micro-array and
sequencing technology, however, large-scale genetic studies are now possible. In the proposed study, we will
enroll a cohort of 4,000 household contacts who have been recently exposed to active TB disease. We will
identify contacts who remain uninfected, despite a well-characterized, high degree of exposure to a TB index
case, and compare them with household contacts who become infected with Mtb. The study will take place in
the high TB incidence settings of India and South Africa. In Aim 1, we will characterize a phenotype for
resistance to Mtb infection using responses to both tuberculin skin test (TST) and interferon-gamma release
assays (IGRA) in a cohort recently exposed to a culture-confirmed active TB index case. By integrating these
TST and IGRA results with rigorous characterization of contacts’ exposure to active TB index cases, we will be
able to identify individuals who have resisted Mtb infection despite a high degree of exposure. In Aim 2, we will
conduct a genome-wide association study (GWAS) to identify common and rare genetic variants associated
with resistance to Mtb infection. We will also investigate the candidate SNPs in previously reported TB-related
genetic loci. In Aim 3, we will leverage the emerging field of metabolomics to identify metabolic profiles that
distinguish individuals resistant to Mtb infection. Identification of metabolic clusters associated with resistance
will reveal cellular pathways involved in resisting or clearing Mtb infection, and will also enhance the GWAS
findings by providing a functional output of the downstream effects of any genetic polymorphisms. This
unbiased and integrated approach will provide an unprecedented opportunity to identify genes and pathways
involved in resistance to Mtb infection, and understand the multi-layered molecular mechanisms underlying TB
infection. Our research team has more than a decade of experience conducting TB, household contact,
genomics and metabolomics studies that will allow us to achieve the innovative s...

## Key facts

- **NIH application ID:** 10208663
- **Project number:** 5R01AI139406-04
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Neel Rajnikant Gandhi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $775,211
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10208663

## Citation

> US National Institutes of Health, RePORTER application 10208663, Characterization of Genomics and Metabolomics among Individuals Highly-Exposed, but resistant to Mtb Infection (5R01AI139406-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10208663. Licensed CC0.

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