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

提案摘要/摘要 据估计，肺炎链球菌每年在全世界造成超过160万人死亡。肺炎球菌疾病 相关死亡在老年人中更为常见。随着抗虫S. 肺炎菌株越来越依赖于有效的肺炎球菌疫苗来保护这种风险 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)来源于23种不同的血清型，因此提供了广泛的覆盖范围， 估计有效性约为65- 70%。尽管如此，随着抗体滴度的降低，保护作用最终会减弱， 通常在免疫后5-10年，并且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，在人类中， 老年男性和女性对肺炎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调查 因此，我们对性别差异如何影响体液免疫的理解存在重大差距。 老年人的免疫力鉴于老年人肺炎球菌疾病的持续负担， 导致对S.对性有强烈考虑的肺炎 偏见早就应该出现了。设计了三个特定的目的来探索调节B细胞免疫的因子， 肺炎球菌多糖和磷酸胆碱（PC）在老年男性和女性。在目标1中，我们 确定年龄和性激素影响发育、表型和功能的程度 B-1 B细胞和PPS 3特异性B细胞的应答。在目标2中，我们将研究有助于 老年男性和女性之间改变的PC特异性B细胞群和天然抗体分泌， 研究这些改变对预防肺炎球菌感染的影响。在目标3中， 将研究性别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别和性别影响在多大程度上 激素相互作用，影响整个生命周期对肺炎球菌保护性免疫力的调节。 我们的研究结果有望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，以及促进接受激素的患者做出知情决策 替代疗法或性别肯定疗法，以便能够最佳地预防肺炎球菌感染， 办妥了一批

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.