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个体的鼻咽部，但仍是主要的呼吸道疾病。 一种在老年人中引起肺炎、败血症和脑膜炎的病原体，尽管有两种 疫苗抗S.肺炎。老年人更容易感染S.肺炎感染是 因为先天免疫和适应性免疫，特别是T细胞介导的功能，随着年龄的增长而下降; 面对S。肺炎感染，老年宿主不能对细菌产生适当的反应， 并且不能控制感染，导致大量的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S。肺炎 感染，并逆转体内T细胞信号传导和增殖中的年龄相关缺陷。T细胞- 依赖性肺炎球菌结合疫苗（PCV-13）对老年人的保护作用似乎高于 T细胞非依赖性肺炎球菌多糖疫苗（PPSV 23）。鼻咽（NP）定植 健康成人和小鼠也作为T细胞依赖性免疫事件，暗示T细胞的关键作用 在针对S.肺炎。为了进一步了解年龄- 先天性和适应性免疫反应的相关缺陷，对这种病原体，S。肺炎因子 在年轻或补充维生素E的老年小鼠中早期存活所需的维生素E，但未治疗的小鼠则不需要。 鉴定，提供了对老年宿主先天免疫选择性压力和缺陷的深入了解（目的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， 老年人（Aim 2）鉴定S.肺炎杆菌生存所需的基因， 免疫活性（年轻小鼠或补充维生素E的老年小鼠）小鼠，但非免疫功能低下的老年小鼠 将使用Tn-seq，一种设计用于鉴定这些因子的高通量遗传选择方法。到 确定维生素E是否通过T细胞依赖机制恢复对老年小鼠的保护，年轻和 喂食对照或补充维生素E饮食的老年小鼠将被S.肺炎或接种疫苗 PCV 13或PSV 23。将通过测量抗-IgG抗体来分析每组中免疫应答的发展。 肺炎球菌抗体滴度和T细胞增殖和分化。最终，S. 肺炎的挑战将提供洞察维生素E的能力，以改善保护性T细胞介导的 老年小鼠的适应性免疫。这项建议旨在进一步调查与年龄相关的缺陷， 对S. pneumoniae和可能影响S.肺炎疫苗 为老年人制定预防肺炎球菌疾病的饮食指南。

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.