Reversing age-related defects in innate and adaptive immune responses to Streptococcus pneumoniae by oral supplementation with vitamin E

项目摘要 肺炎链球菌通常定植于健康人的鼻咽，但它是一种主要的呼吸道细菌。 老年人中引起肺炎、败血症和脑膜炎的病原体，尽管有两种 肺炎链球菌疫苗。老年人更容易感染肺炎链球菌的一个原因是 因为先天免疫和获得性免疫，特别是T细胞介导的功能，随着年龄的增长而下降； 面对肺炎链球菌的感染，年老的宿主无法对细菌做出适当的反应。 并且未能控制感染，导致大量肺部炎症和侵袭性疾病。 重要的是，口服补充维生素E可以逆转年龄驱动的肺炎链球菌的易感性 并逆转体内与衰老相关的T细胞信号转导和增殖缺陷。T细胞- 依赖肺炎球菌结合疫苗(PCV13)似乎为老年人提供了比 T细胞非依赖性肺炎球菌多糖疫苗(PPSV23)。鼻咽部(NP)的定植 健康的成年人和小鼠也是T细胞依赖的免疫事件，这意味着T细胞的关键作用 在针对肺炎链球菌的适应性免疫反应的发展过程中。为了进一步了解年龄- 针对肺炎链球菌因子的先天和获得性免疫反应的相关缺陷 年轻或补充维生素E的老年小鼠早期存活所需的，但不是未经治疗的小鼠 识别，提供对老年宿主先天免疫选择压力和缺陷的洞察(目标1)， 并将确定补充维生素E是否能逆转T细胞功能和分化的缺陷 一位年迈的东道主(目标2)。鉴定肺炎链球菌生存所需的基因类别 免疫功能正常(幼鼠或补充维生素E的老年)小鼠，但免疫功能未受损，老年 老鼠，TN-seq，一种高通量的基因选择方法，旨在识别这些因素，将被利用。至 确定维生素E是否通过T细胞依赖机制恢复对衰老小鼠的保护 喂食对照或补充维生素E的老年小鼠将被肺炎链球菌定植或接种疫苗 使用PCV13或PPSV23。每组的免疫反应的发展将通过测量抗- 肺炎球菌抗体滴度与T细胞增殖分化的关系最终，S。 肺炎挑战将提供关于维生素E提高T细胞介导的保护性能力的洞察力 老龄小鼠的获得性免疫。这项建议旨在进一步调查与年龄相关的缺陷 肺炎链球菌的先天和获得性免疫反应及其对肺炎链球菌疫苗的影响 制定和制定老年人预防肺炎球菌病的饮食指南。

Project Summary Streptococcus pneumoniae normally colonizes the nasopharynx of healthy individuals yet is a major respiratory pathogen among the elderly that causes pneumonia, septicemia, and meningitis, despite the availability of two vaccines against S. pneumoniae. One reason the elderly are more susceptible to S. pneumoniae infection is because innate and adaptive immunity, particularly that of T cell-mediated function, declines with age; when faced with S. pneumoniae infection, the aged host cannot mount an appropriate response against the bacteria and fails to control the infection, resulting in large amounts of pulmonary inflammation and invasive disease. Importantly, oral supplementation with vitamin E can reverse the age-driven susceptibility to S. pneumoniae infection in aged mice, and reverses age-related defects in T cell signaling and proliferation in vivo. The T cell- dependent pneumococcal conjugate vaccine (PCV13) appears to provide higher protection to the elderly than the T cell-independent pneumococcal polysaccharide vaccine (PPSV23). Nasopharyngeal (NP) colonization in healthy adults and mice also acts as a T cell-dependent immunizing event, implicating the critical role of T cells during development of an adaptive immune response against S. pneumoniae. To further understand age- related defects of innate and adaptive immune responses against this pathogen, S. pneumoniae factors required for early survival in young or vitamin E-supplemented aged mice but not untreated mice will be identified, providing insight into the innate immune selective pressures and defects of an aged host (Aim 1), and it will be determined if vitamin E supplementation reverses defects of T cell function and differentiation in an aged host (Aim 2). To identify classes of S. pneumoniae genes that are required for survival in immunocompetent (young mice or vitamin E-supplemented aged) mice but not immunocompromised, aged mice, Tn-seq, a high-throughput genetic selection method designed to identify these factors, will be utilized. To determine if vitamin E restores protection to aged mice through a T cell-dependent mechanism, young and aged mice fed a control or supplemented vitamin E diet will be NP colonized with S. pneumoniae or vaccinated with PCV13 or PPSV23. Development of immune responses in each group will be analyzed by measuring anti- pneumococcal antibody titers and T cell proliferation and differentiation. Ultimately, disease outcome after S. pneumoniae challenge will provide insight on the ability of vitamin E to improve protective T cell-mediated adaptive immunity in aged mice. This proposal aims to further investigate the age-associated defects of the innate and adaptive immune responses to S. pneumoniae and may impact S. pneumoniae vaccine development and dietary guidelines for older adults to prevent pneumococcal disease.