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: 10532071
• 负责人: Karen M Haas
• 金额: $ 53.2万
• 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/10532071
• 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; Centers for Disease Control and Prevention (U.S.); 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; Lead; Longevity; Modeling; Mucous Membrane; Mus; Patients; Phenotype; Phosphorylcholine; Physiological; Play; Pneumococcal Infections; Pneumococcal Pneumonia; Pneumococcal vaccine; Pneumonia; Polysaccharides; Population; Populations at Risk; Public Health; Regulation; Research; Risk; Serotyping; Sex Bias; Sex Differences; Streptococcus pneumoniae; Testing; Transcription Alteration; Vaccination; Vaccines; Women' s Role; age effect; age related; aged; aging population; base; biological sex; capsule; design; 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，肺炎链球菌在全球范围内造成超过160万人死亡。肺炎球菌疾病 与老年人相关的死亡更为频繁。抗生素耐药性S.的出现日益增长。 肺炎菌株会增加对有效肺炎球菌疫苗的依赖，以保护这种处于危险中 人口。当前在成年人中使用的天然肺炎球菌疫苗由囊囊多糖组成 （PPS）源自23种不同的血清型，因此提供了针对侵入性疾病的广泛覆盖范围 估计的疗效约为65-70％。尽管如此，随着抗体滴度的减少，保护最终会减弱， 免疫后5 - 10年，对肺炎的保护是有限的。优化保护性 因此，老年人的疫苗反应是一个主要目标。但是，在人类中有明显的差异 关于肺炎球菌多糖的体液反应，老年男性和女性之间 抗原。我们发现在小鼠中也是如此。这些差异的原因未被调查 因此，在我们对与性别相关的差异如何影响体液的理解中凸显了一个很大的差距 老年人的免疫力。鉴于老年人中肺炎球菌疾病的持续负担 有助于改变对肺炎链球菌的免疫力的基本因素，对性别有很大的考虑 偏见很早就应该了。设计三个特定目的是为了探测调节B细胞免疫力的因素 老年男性和女性的肺炎球菌多糖和磷酸胆碱（PC）。在AIM 1中，我们将 确定年龄和性激素在多大程度上影响发展，表型和功能 B-1B细胞和PPS3特异性B细胞的反应。在AIM 2中，我们将调查导致的机制 老年男性和女性之间的PC特异性B细胞群体和天然抗体分泌改变改变 检查这些改变对肺炎球菌感染的影响所带来的后果。在AIM 3中，我们 将研究性驱动的差异影响对S的保护性粘膜反应的程度。 肺炎。因此，我们的研究将研究生物学性别和性别影响的程度 激素相交以影响整个生命周期的保护性肺炎球菌免疫的调节。 预计我们的结果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，并为接受激素的患者促进明智的决策 替代或性别肯定疗法，使得对肺炎球菌感染的最佳保护可以是 成就了。