Genetic and hormonal mechanisms underlying sex-specific immune responses in tuberculosis

Abstract

Tuberculosis (TB), the world's deadliest bacterial infection, afflicts more human males than females, with a male/female (M/F) ratio of 1.7. Sex disparities in TB prevalence, pathophysiology, and clinical manifestations are widely reported, but the underlying biological mechanisms remain largely undefined. This review assesses epidemiological data on sex disparity in TB, as well as possible underlying hormonal and genetic mechanisms that might differentially modulate innate and adaptive immune responses in males and females, leading to sex differences in disease susceptibility. We consider whether this sex disparity can be extended to the efficacy of vaccines and discuss novel animal models which may offer mechanistic insights. A better understanding of the biological factors underpinning sex-related immune responses in TB may enable sex-specific personalized therapies for TB.

Keywords: TB immune responses; X chromosome inactivation escape; X-linked microRNAs; four core genotypes; sex chromosomes; sex differences; sex hormones; tuberculosis.

Figure 1.. Sex hormone effects that may contribute to the male bias in immune responses to tuberculosis.

Effects of estrogen and testosterone on human or mice immune cells that are known to play a key role in anti-tuberculosis (TB) immunity [31,73]. Center panel: depiction of the global sex- and age-based distribution of TB mortality in 2020 (adapted from the 2021 WHO TB report) [1]. Schematic representation, images not scaled. Abbreviations: IFN-γ, interferon γ; TNF-α, tumor necrosis factor α; NO, nitric oxide; Ca²⁺, calcium ion, cAMP, Cyclic Adenosine Monophosphate; MAPK/ERK, mitogen-activated protein kinase/Extracellular signal-regulated kinase 1/2; PI3K/AKT, phosphatidylinositol 3-kinase/protein kinase B; iNOS, nitric oxide synthase; TLR-4, toll-like receptor 4, IL-4, interleukin 4; IL-10, interleukin 10; IgG, immunoglobulin G; IgM, immunoglobulin M; T_reg, regulatory T cell; CD, cluster of differentiation; Th, T helper cell; IL-1β, interleukin 1β; CCL2, chemokine (C-C motif) ligand 2; IL-6, interleukin 6; DCs, dendritic cells, MDSCs, Myeloid-derived suppressor cells; NK cells, natural-killer cells.

Figure 2.. Various genetic events that may regulate male sex bias in anti-tuberculosis immunity.

Key genetic determinants on sex chromosomes with potential roles in susceptibility to TB infection, as reported in mice or human studies. Schematic representation, images not scaled. Abbreviations: Mb, million base pairs; TFs, transcription factors; CD40L, CD40 ligand; FOXP3, Forkhead box P3; IRAK1, Interleukin-1 receptor-associated kinase 1; CYBB, Cytochrome b-245 beta chain; IL-13RA1, interleukin 13 receptor alpha 1; BTK, Bruton’s tyrosine kinase; RPS6KA3, Ribosomal Protein S6 Kinase A3; DDX3X, DEAD-Box Helicase 3 X-Linked; CXCR3, C-X-C Motif Chemokine Receptor 3; LAMP-2, lysosomal associated membrane protein-2; PMN, Polymorphonuclear neutrophils; PD-L1, Programmed death-ligand 1.