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

高龄和性别对肺炎链球菌体液免疫的影响

• 批准号: 10693951
• 负责人: Karen M Haas
• 金额: $ 53.34万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693951
• 关键词: Adult; Advisory Committees; Age; Aging; Antibiotic Resistance; Antibodies; Antibody Formation; Antibody Response; Antibody titer measurement; Antigens; B-Lymphocytes; Bacteremia; C57BL/6 Mouse; Cell Wall; Cells; Cessation of life; Decision Making; Development; Disease; Elderly; Estrogens; Female; Future; Gender; Global Change; Goals; Gonadal Steroid Hormones; Hormones; Human; Humoral Immunities; Immune system; Immunity; Immunization; Immunoglobulin G; Immunoglobulin M; Infection; Investigation; Knowledge; Longevity; Modeling; Mucous Membrane; Mus; Patients; Phenotype; Phosphorylcholine; Physiological; Play; Pneumococcal Infections; Pneumococcal Pneumonia; Pneumococcal vaccine; Pneumonia; Pneumovax; Polysaccharides; Polyvalent pneumococcal vaccine; Population; Populations at Risk; Public Health; Reaction; Recommendation; Regulation; Research; Role; Serotyping; Sex Bias; Sex Differences; Streptococcus pneumoniae; Testing; Transcription Alteration; Vaccination; Vaccines; age effect; age related; aged; aging population; biological sex; capsule; design; gender affirmation; gender affirming therapy; improved; male; middle age; mouse model; mucosal vaccine; natural antibodies; prevent; rational design; response; sex; vaccine response; vaccine strategy

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.

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 与此相关的死亡在老年人中更为常见。抗生素耐药性链球菌的不断出现。 肺炎球菌菌株越来越依赖有效的肺炎球菌疫苗来保护这种高危人群 人口。目前成人使用的天然肺炎球菌疫苗由荚膜多糖组成 (PPS) 源自 23 种不同的血清型，因此可提供广泛的侵袭性疾病覆盖范围 预计疗效约为 65-70%。尽管如此，随着抗体滴度的降低，保护作用最终会减弱， 通常是在免疫后 5-10 年，对肺炎的保护作用有限。优化防护 因此，老年人的疫苗反应是一个主要目标。然而，人类之间存在明显差异 老年男性和女性对肺炎球菌多糖的体液反应 抗原。我们发现小鼠身上也有同样的情况。这些差异的原因尚未得到调查 因此凸显了我们对性别相关差异如何影响体液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，一项调查 导致对肺炎链球菌免疫力改变的潜在因素，并强烈考虑性别 偏见早就该出现了。设计了三个具体目标来探索调节 B 细胞免疫的因素 老年男性和女性的肺炎球菌多糖和磷酸胆碱（PC）。在目标 1 中，我们将 确定年龄和性激素影响发育、表型和功能的程度 B-1b 细胞和 PPS3 特异性 B 细胞的反应。在目标 2 中，我们将研究有助于实现这一目标的机制。 改变了老年男性和女性之间的 PC 特异性 B 细胞群和天然抗体分泌， 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 将研究性别驱动的差异在多大程度上影响对金黄色葡萄球菌的保护性粘膜反应。 肺炎杆菌。因此，我们的研究将调查生物性别和性别影响的程度 激素相互作用，影响整个生命周期中保护性肺炎球菌免疫的调节。 我们的结果预计将对性别和年龄的未来设计和管理产生重大影响 适当的疫苗，并促进接受激素治疗的患者做出明智的决策 替代疗法或性别确认疗法，从而可以针对肺炎球菌感染提供最佳保护 实现了。