# Genetic and hormonal mechanisms mediating sex differences in TB and TB-HIV

> **NIH NIH R37** · JOHNS HOPKINS UNIVERSITY · 2022 · $813,838

## Abstract

PROJECT SUMMARY
Tuberculosis (TB) occurs more frequently in males (~70% of cases) than females. While reduced access to care
for females and undercounting of female cases may contribute modestly to this longstanding epidemiologic
observation in some countries, both human studies (the Lűbeck disaster and eunuch studies) as well as animal
models underscore the fact that biological factors play a dominant role in female resistance to TB. Despite the
importance of this sex-bias in TB, it has gone largely neglected by basic science researchers. The central
scientific premise of this application is that defining the biological mechanisms of the male bias for TB will
enlighten our mechanistic understanding of TB pathogenesis and protective human immune responses in TB. A
multidisciplinary team with decades of expertise on sex differences (Klein), TB pathogenesis (Bishai), and sex
differences in HIV (Scully) will conduct the project.
This proposal will investigate the impact of genetics (X chromosome complement) and sex steroid hormones
on TB pathogenesis using cellular tools, animal models, and human samples. A key tool used in Aim 1 will be
the novel four core genotype (FCG) mouse model, in which animals with XX genotypes have male
gonads/hormone levels and those with XY genotypes have female gonads/hormone levels. This model will
enable us to differentiate the impact of genetics from those of the sex steroids on murine control of TB.
The X chromosome encodes numerous genes of immunologic importance including the genes that encode for
TLR7, TLR8, CYBB, NEMO, CD40L, and FOXP3. The process of X-chromosome inactivation (XCI)--in which
one female X chromosome is epigenetically silenced--is designed to provide balanced gene dosing between
females and males. Certain genes, however, can escape XCI, leading to a double gene dose in females. The
process of gene escape from XCI has not been studied in the context of TB, and advanced molecular tools will
be used in Aim 2 to investigate gene escape from XCI as a cause of the male bias in severity of TB.
While it is widely known that sex steroid signaling modulates immune function, the impact of sex steroids as a
basis for the male bias in TB has not been thoroughly investigated. Testosterone has an immunotolerizing effect,
reducing levels of IFN-γ and elevating levels of IL-4. In contrast, estrogen promotes higher levels of macrophage
activation and increases in TNF-α levels. In Aim 2, we will carefully dissect the role of sex steroids using adoptive
transfer methods as well as gonadectomized mice with selective hormone replacement.
Lastly, in Aim 3 we will extend these studies to assess the intersection of HIV infection, a critical risk for TB, and
sex differences in immunity. We will assess immune responses in samples from people living with HIV (PLWH)
on ART versus healthy controls (HCs), specifically balancing groups for sex. We will evaluate the ability of whole
blood and hMDM from PLWH and HCs to contain Mtb...

## Key facts

- **NIH application ID:** 10484064
- **Project number:** 1R37AI167750-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** WILLIAM Ramses BISHAI
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $813,838
- **Award type:** 1
- **Project period:** 2022-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10484064

## Citation

> US National Institutes of Health, RePORTER application 10484064, Genetic and hormonal mechanisms mediating sex differences in TB and TB-HIV (1R37AI167750-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10484064. Licensed CC0.

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