Study Links Gonadal Sex to TB Susceptibility Through Immune Response Differences
A mouse study using a genetic model that separates gonadal sex from chromosomal sex found that gonadal males develop more severe tuberculosis due to dysfunctional myeloid immune responses, while gonadal females — especially XX females — showed the greatest resistance. Researchers used Four Core Genotype mice to isolate the effects of testes and ovaries from X and Y chromosome influences, finding that androgens and testes drive excessive neutrophil activity, disorganized granulomas, and hyperinflammation. The findings offer a mechanistic explanation for the well-documented human sex disparity in TB, where males account for a disproportionate share of cases and deaths.
Tuberculosis kills more males than females globally, with a male-to-female ratio exceeding 1.7, but the biological mechanisms behind this disparity have remained poorly understood. Using Four Core Genotype (FCG) mice — a model that allows researchers to independently vary gonadal sex (testes or ovaries) and chromosomal sex (XX or XY) — the study found that gonadal males, regardless of whether they carried XX or XY chromosomes, experienced accelerated disease, higher bacterial burden, and more severe lung pathology. The male susceptibility was mechanistically linked to early myeloid immune priming, excessive neutrophil recruitment, accumulation of CCR2+ monocytes, enhanced neutrophil extracellular trap (NET) formation, and disorganized granulomas — pointing to hyperinflammation rather than a failure to detect the bacteria. Conversely, gonadal females showed greater resistance, with XX gonadal females exhibiting the strongest protection, associated with well-coordinated T- and B-cell responses and enhanced B-cell follicle formation. XY gonadal females were less resistant than XX gonadal females, suggesting that chromosomal sex also plays a modulatory role on top of gonadal effects. The study identifies gonad-driven myeloid dysregulation — likely mediated by androgens — as a central mechanism underlying male TB susceptibility, with potential implications for sex-informed therapeutic strategies.
What's missing
As a preprint, this study has not yet undergone peer review. The research is conducted entirely in mice, and it remains unclear how directly the FCG model findings translate to human immunology and TB pathogenesis. The study does not directly measure androgen levels or test androgen-blocking interventions, leaving the causal role of specific androgens (e.g., testosterone) inferential rather than experimentally confirmed. Additionally, the relative contributions of gonadal hormones versus other gonad-derived signals are not fully resolved.
What different sources said
- bioRxivCenter
Gonadal regulation of sex-specific immunity in tuberculosis: enhanced lymphocyte function in females and dysfunctional myeloid responses in males
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