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

结核分枝杆菌易感性的宿主决定因素：生物性别的作用

• 批准号: 436203168
• 负责人: Dr. Bianca Schneider
• 金额: --
• 依托单位: Forschungszentrum Borstel - Leibniz Lungenzentrum
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/436203168?language=en
• 关键词: Host; determinants; susceptibility; Mycobacterium; tuberculosis

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.

男性结核病患病率明显高于女性。性别和性别相关因素都可能导致男性结核病发病率较高，但后者的作用在很大程度上被忽视了。我们实验室的研究表明，与雌性小鼠相比，雄性 C57BL/6 小鼠对结核分枝杆菌 (Mtb) H37Rv 的易感性增加，表现为疾病进展加速和过早死亡。男性的过早死亡与两性之间肉芽肿性病变质量的显着差异有关。与小鼠和人类的结核病保护相关的异位淋巴结构在雄性中要小得多。与此一致的是，CXCL13（通过协调表达 CXCR5 的淋巴细胞归巢到滤泡区域来参与淋巴新生）和 IL-23（在 Mtb 感染期间刺激 CXCL13 表达）在男性肺中显着较低。因此，我们的数据表明，男性肺部感染 Mtb H37Rv 后异位淋巴结构的形成受损。 H37Rv 并不是当今相关的 Mtb 流行菌株，但北京谱系的菌株正在世界范围内出现。在免疫学上，H37Rv 和 HN878（研究最充分的北京分离株）之间的一个重要区别是诱导 IL-17 反应。 IL-17 不仅介导针对 HN878 的早期保护，而且通过诱导 CXCL13 指导 T 细胞在肺淋巴滤泡内定位，在疫苗诱导的针对 Tb 的免疫中发挥关键作用。感染 HN878 后，男性死亡时间明显早于女性。值得注意的是，与女性相比，男性的 IL-17A 表达显着降低，淋巴滤泡也小得多。睾酮已被描述为下调 IL-17 的产生并减弱 Th17 反应。因此，我们假设睾酮通过干扰这一参与淋巴滤泡形成的关键免疫途径来促进男性结核病的发展，从而损害对结核分枝杆菌感染的控制。该提案的主要目的是确定睾酮对结核分枝杆菌保护性免疫反应的影响。具体来说;我们将研究其对 HN878 感染后 IL-17A 产生和异位淋巴结构形成的潜在抑制作用。此外，我们将研究男性和女性对结核病易感性的差异是否会转化为女性疫苗诱导的优越保护，以及我们是否可以通过联合雄激素剥夺疗法来增强男性疫苗的功效。这项研究的结果将表明，与淋巴滤泡形成相关的分子途径如何在性别之间受到不同的调节，以及对受结核分枝杆菌感染的肺部保护性免疫反应的发展和维持的影响。这种理解可能对设计新的疫苗策略产生深远的影响，以在未来充分保护男女免受结核分枝杆菌的侵害。