Sex as a Biological Variable in Tuberculosis Pathogenesis

Tuberculosis (TB) remains a leading cause of infectious mortality worldwide, disproportionately affecting vulnerable populations and posing significant challenges for global health. Sex profoundly influences TB susceptibility, disease progression, treatment outcomes, and drug pharmacokinetics. While biological factors such as sex hormones and, to some extent, sex chromosomes are suspected drivers, the mechanisms behind these sex-based differences remain poorly understood. Emerging evidence indicates that males experience higher TB incidence, more severe disease, and worse treatment outcomes, including higher rates of relapse, treatment failure, and death, while females often achieve better drug exposure and display stronger immune responses. Differences in adverse drug reactions and pharmacokinetics also vary greatly by sex, suggesting potential for personalized, optimized therapy. These findings raise important questions: How does sex intersect with TB pathogenesis, drug metabolism, and resistance? Could integrating sex-specific strategies improve TB management and global control efforts? Understanding these differences is crucial to unravel the hidden drivers of TB vulnerability and to develop sex-specific, tailored therapies and precision interventions.