Host determinants of susceptibility to Mycobacterium tuberculosis: the role of the biological sex

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TB prevalence is significantly higher among men than women. Both gender- and sex-related factors likely contribute to higher Tb rates in men but the role of the latter has been largely ignored. Studies in our lab revealed an increased susceptibility of male C57BL/6 mice towards Mycobacterium tuberculosis (Mtb) H37Rv, reflected by accelerated disease progression and premature death compared to females. Premature death of males was associated with striking differences in the quality of the granulomatous lesions between the sexes. Ectopic lymphoid structures, associated with protection in Tb in mice and man, were much smaller in size in males. In line with this, expression of CXCL13, which is involved in lymphoid neogenesis by orchestrating the homing of CXCR5 expressing lymphocytes to the follicular areas, and IL-23 which stimulates CXCL13 expression during Mtb infection were significantly lower in the male lung. Hence, our data indicate impaired formation of ectopic lymphoid structures upon infection with Mtb H37Rv in male lungs. H37Rv is not a relevant Mtb circulating strain today but strains of the Beijing lineage are emerging worldwide. Immunologically one important difference between H37Rv and HN878, the best studied Beijing isolate, is the induction of IL-17 responses. IL-17 not only mediates early protection against HN878 but also has a critical role in vaccine-induced immunity against Tb via the induction of CXCL13 to instruct the localization of T cells within lung lymphoid follicles. Upon HN878 infection, males succumbed to infection significantly earlier than females. Of note, IL-17A expression was significantly reduced and lymphoid follicles were much smaller in males compared to females. Testosterone has been described to downregulate the production of IL-17 and to attenuate Th17 responses. Therefore we hypothesize that testosterone promotes Tb disease development in males by interfering with this critical immune pathway involved in lymphoid follicle formation, thereby impairing control of Mtb infection. The main objective of this proposal is to determine the effect of testosterone on protective immune responses to Mtb. Specifically; we will investigate its potential inhibitory effect on IL-17A production and the formation of ectopic lymphoid structures upon HN878 infection. Moreover, we will investigate whether the difference in susceptibility to Tb in males and females translates into superior vaccine induced protection in females, and if we can enhance vaccine efficacy in males by combined androgen-deprivation therapy. Findings from this research will show how molecular pathways associated with lymphoid follicle formation are differently regulated between the sexes and impact on the development and maintenance of protective immune responses in the Mtb-infected lung. This understanding may have far reaching implications for the design of novel vaccine strategies to adequately protect both sexes against Mtb in the future.