# Human Genetic Dissection of Exit from Latency in Tuberculosis

> **NIH NIH U19** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $610,909

## Abstract

Only a minority of individuals with latent Mycobacterium tuberculosis (Mtb) infection (~5%) develop TB
disease, typically pulmonary TB (PTB), due to the reactivation of dormant mycobacteria. There is growing
genetic epidemiological evidence that PTB has a strong genetic component in humans, but the molecular
basis of susceptibility to Mtb reactivation remains largely unknown. Candidate gene and genome-wide (GW)
association studies have suggested that common variants play only a modest role in the genetics of PTB, or
that their role is restricted to specific subgroups. We recently showed, by an unbiased GW linkage approach,
that common variants of TOX, a gene involved in T-cell and NK-cell development, are associated with PTB
in young patients with a short latency duration, in two ethnically different populations. Genetic factors other
than TOX may also contribute to PTB, including rare variants of unknown genes. Our project will combine a
focused in-depth dissection of the role of TOX in PTB, based on both human and mouse studies, with a GW
approach investigating the role of rare variants in PTB. Study subjects will be recruited in Haiti, through the
GHESKIO Center, to establish a large case/control sample (HIV-negative and HIV-positive), and a family-based
sample with at least two PTB-affected siblings. We will conduct a comprehensive association study of
PTB with TOX polymorphisms, and a GW search for rare variants in PTB patients, based on a combination
of GW linkage and whole-exome sequencing studies. All variants consistently found to be associated with
PTB will be validated immunologically, at the molecular and cellular levels with cutting-edge techniques. We
will study the functional impact of previously identified variants located in the 3' region of TOX on T-cell
immunity, both in vitro in human cells, and in vivo in mice. Mouse models will be used to investigate the role
of TOX in T-cell responses to Mtb infection, together with analyses of endogenous T-cell responses in mice
with T cell-specific TOX gene deletion. Our preliminary data indicate that TOX is strongly expressed in
human CD4, Treg, NK, and γδT cells and in murine CD4 and Treg cells, and that the 3' end of TOX probably
has regulatory activities, further supporting the candidacy of TOX as a prime regulator of PTB immunity.

## Key facts

- **NIH application ID:** 10057811
- **Project number:** 5U19AI111143-07
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Jean-Laurent Casanova
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $610,909
- **Award type:** 5
- **Project period:** 2014-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10057811

## Citation

> US National Institutes of Health, RePORTER application 10057811, Human Genetic Dissection of Exit from Latency in Tuberculosis (5U19AI111143-07). Retrieved via AI Analytics 2026-06-03 from https://api.ai-analytics.org/grant/nih/10057811. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*