THE IMPACT OF ADVANCED AGE AND SEX ON HUMORAL IMMUNITY TO STREPTOCOCCUS PNEUMONIAE

建议书摘要/摘要 据估计，全世界每年有160多万人死于肺炎链球菌。肺炎球菌病 而相关死亡在老年人中要频繁得多。对抗生素产生抗药性的S。 肺炎菌株越来越依赖有效的肺炎球菌疫苗来保护这种高危状态 人口。目前用于成人的天然肺炎球菌疫苗由荚膜多糖组成。 (PPS)来自23个不同的血清型，因此提供了广泛的覆盖范围，以防止侵袭性疾病 估计有效率为65-70%。尽管如此，随着抗体效价的降低，保护性最终会减弱， 通常在免疫后5-10年，对肺炎的保护是有限的。优化保护 因此，老年人的疫苗反应是一个主要目标。然而，在人类身上有明显的差异。 老年男性和女性对肺炎链球菌多糖的体液反应 抗原。我们在老鼠身上也发现了同样的情况。这些差异的原因还没有得到调查。 因此突显了我们对与性别相关的差异如何影响幽默的理解上的一个重大差距 老年人享有豁免权。鉴于肺炎球菌病在老年人中的持续负担，一项关于 肺炎链球菌免疫力改变的潜在因素与性别有关 偏见早就该出现了。设计了三个特定的目标来探索调节B细胞免疫的因素 老年男女肺炎球菌多糖和磷胆碱(PC)在目标1中，我们将 确定年龄和性激素对发育、表型和功能的影响程度 B-1b细胞和PPS3特异性B细胞的反应。在目标2中，我们将调查有助于 老年男女之间PC特异性B细胞群和自然抗体分泌的变化 检查这些改变对预防肺炎球菌感染的影响。在目标3中，我们 将调查性别驱动的差异在多大程度上影响对S. 肺炎。因此，我们的研究将调查生物性行为和性别影响的程度 荷尔蒙相互交织，在整个生命周期内影响保护性肺炎球菌免疫的调节。 我们的结果预计将对未来性别和年龄的设计和管理产生重大影响。 适当的疫苗，以及促进接受激素治疗的患者的知情决策 替代疗法或性别肯定疗法，以便对肺炎球菌感染的最佳保护可以是 已实现。

PROPOSAL SUMMARY/ABSTRACT Streptococcus pneumoniae is estimated to cause over 1.6 million deaths/year worldwide. Pneumococcal disease and related deaths are much more frequent in the elderly. The growing emergence of antibiotic-resistant S. pneumoniae strains places increasing reliance on effective pneumococcal vaccines to protect this at-risk population. The native pneumococcal vaccine currently used in adults consists of capsular polysaccharides (PPS) derived from 23 different serotypes and therefore provides broad coverage against invasive disease with an estimated efficacy of ~65-70%. Nonetheless, protection eventually wanes as antibody titers diminish, typically by 5-10 years post-immunization, and protection against pneumonia is limited. Optimizing protective vaccine responses in the elderly is therefore a major goal. However, in humans there are clear differences between elderly males and females with respect to humoral responses to pneumococcal polysaccharide antigens. We have found the same to be true in mice. The cause of these differences has gone uninvestigated and therefore highlights a significant gap in our understanding of how sex-related differences impact humoral immunity in the aged. Given the continued burden of pneumococcal disease in the elderly, an investigation of the underlying factors contributing to altered immunity to S. pneumoniae with a strong consideration for sex bias is long overdue. Three specific aims are designed to probe factors regulating B cell immunity to pneumococcal polysaccharides and phosphorylcholine (PC) in aged males and females. In Aim 1, we will determine the extent to which age and sex hormones impact the development, phenotype, and functional responses of B-1b cells and PPS3-specific B cells. In Aim 2, we will investigate the mechanisms contributing to altered PC-specific B cell populations and natural antibody secretion between aged males and females and examine the consequences these alterations have for protection against pneumococcal infections. In Aim 3, we will investigate the extent to which sex-driven differences impact protective mucosal responses to S. pneumoniae. Our studies will thereby investigate the extent to which biological sex and gender-influencing hormones intersect to impact the regulation of protective pneumococcal immunity throughout the lifespan. Our results are expected to have a significant impact on the future design and administration of sex- and age- appropriate vaccines, as well as promote informed decision-making for patients receiving hormone replacement or gender-affirming therapy, such that optimal protection against pneumococcal infections can be achieved.