Respiratory mucosal immune development in early life and the quest for protective local memory against respiratory syncytial virus.

项目摘要 呼吸道合胞病毒（Respiratory syncytial virus，RSV）是全球范围内引起下呼吸道感染的最重要病原体 疾病在生命的第一年，并且没有疫苗。以前的疫苗策略导致严重的 婴儿疫苗接种者初次感染RSV疾病。在过去的60年里， 失败了因此，我们建立了一个新生鼠RSV模型， 针对RSV的免疫应答。我们的首要目标是确定年龄依赖性的粘膜免疫调节 适应性免疫细胞，导致对RSV的易感性，并可以针对精确设计疫苗， 婴儿。组织驻留记忆T细胞最近被发现提供杀菌保护， 对感染做出快速反应。在鼠模型中，CD 8 T细胞对于RSV清除是关键的，并且是 与人类中病毒减少和寄生虫学降低相关。我们的研究和其他节目的研究 新生儿的CD 8 T细胞反应通常比成年人减少，并且难以分化为记忆。 细胞RSV特异性组织驻留记忆T细胞（TRM）如何在婴儿中发育，以及它们是否可以被诱导 提供保护是未知的。以前的疫苗没有针对这种新发现的T细胞亚群， 还没有被用于疫苗设计。我们要检验的中心假设是新生儿RSV特异性T细胞 TRM细胞分化不良，导致保护性免疫力低下，但增强先天免疫力 活化可以改善新生儿RSV特异性T细胞定位于呼吸道粘膜， 保护性RSV特异性TRM。提出了三个具体目标来检验这一假设，其目标是确定 为新生儿设计的RSV疫苗的新免疫靶点。创新实验的建议 方法被设计为：（1）确定新生儿先天免疫应答的要求，以提供 抗原和/或T细胞活化以建立RSV特异性TRM，（2）鉴定亚特化抗原呈递 诱导RSV特异性TRM的细胞以及如何增强APC活化以保留RSV特异性记忆CD 8 T 呼吸道粘膜中的细胞，（3）确定RSV表位特异性TRM保护免受RSV感染的作用。 这些研究将确定疫苗设计的关键组成部分，包括抗原的可用性和关键因素。 靶向抗原呈递细胞，以便在新生儿中产生RSV特异性TRM，在攻击时提供保护。

PROJECT SUMMARY Globally, respiratory syncytial virus (RSV) is the single most important pathogen causing lower respiratory tract disease in the first year of life, and for which there is no vaccine. Previous vaccine strategies resulted in severe RSV disease in infant vaccine recipients upon primary infection. Over the past 60 years subsequent vaccines have failed. We, therefore, developed a neonatal murine model of RSV to interrogate the respiratory mucosal immune response against RSV. Our overarching goal is to identify age-dependent immune regulation of mucosal adaptive immune cells that results in susceptibility to RSV and can be targeted to precisely design vaccines for infants. Tissue-resident memory T cells have recently been discovered to provide sterilizing protection against influenza by rapidly responding to infection. CD8 T cells are critical for RSV clearance in murine models and are associated with reduction of virus and reduced symptomatology in humans. Our research and that of other show that neonatal CD8 T cell responses are often reduced compared to adults and poorly differentiate into memory cells. How RSV-specific tissue-resident memory T cells (TRM) develop in infants and if they can be induced to provide protection is unknown. Prior vaccines have not targeted this newly discovered T cell subset and they have not been explored for vaccine design. Our central hypothesis to be tested is that neonatal RSV-specific T cells poorly differentiate into TRM resulting in poor protective immunity, but that enhancing innate immune activation can improve neonatal RSV-specific T cell localization to the respiratory mucosa and establish protective RSV-specific TRM. Three Specific Aims are proposed to test this hypothesis, with the goal of identifying novel immune targets for RSV vaccines designed for neonates. The proposed innovative experimental approaches are designed to: (1) identify the requirements of the neonatal innate immune response to provide antigen and/or T cell activation to establish RSV-specific TRM, (2) identify the subspecialized antigen presenting cells that induce RSV-specific TRM and how to enhance APC activation to retain RSV-specific memory CD8 T cells in the respiratory mucosa, (3) define the role of RSV-epitope specific TRM to protect against RSV infection. These studies will define the key components of vaccine design including antigen availability and the critical antigen presenting cells to target in order to develop RSV-specific TRM in neonates that protect upon challenge.