Restimulating memory T cell responses in elderly by a novel, live influenza vaccine

流感病毒的呼吸道感染导致人类严重的发病率和死亡率， 动物世界重要的是，在人类中，流感后的大多数发病率和死亡率 感染见于老年人（> 65岁）。然而，清楚地了解衰老是如何 对先天免疫反应的影响，以及如何改善该年龄组的疫苗设计， 缺乏针对流感病毒中保守表位再刺激预先存在的记忆T细胞 可能会给这个年龄段的人带来保护性免疫力。老年人理想的疫苗应 因此参与激活抗原呈递细胞的模式识别受体（PRRs） 在一些实施方案中，抗原表位（APC）产生保守的抗原表位，同时避免明显的炎症反应。在 第一阶段，我们发现M2SR病毒导致记忆性CD4和CD8 T细胞的稳健再刺激， 老年人中的细胞，而不会通过接合非炎性体引起病理性炎症 依赖先天途径。在第二阶段的提案中，我们将探讨M2SR如何刺激 老年受试者的抗病毒免疫应答，目的如下： 目标1。检查树突状细胞的存活和功能，以应对M2SR感染。 目的2：探讨干扰素刺激基因表达调控的分子机制 在树突细胞中。 目的3：评价接种M2SR疫苗的人类受试者的早期免疫应答。 这些实验旨在改善老年人对流感介导的 疾病，通过了解基本的先天免疫缺陷，导致失败， 安装保护性免疫。实验结果预计将产生重大影响， 这两个方面的基本理解的潜在机制流感相关的 疾病的易感老年人口，并提供了一个基础， 疫苗和免疫干预。

Respiratory infections with influenza viruses cause severe morbidity and mortality in humans and animals worldwide. Importantly, in humans, the majority of morbidity and mortality following flu infection is seen in older individuals (> 65 years old). Yet, clear understanding of how aging impacts on innate immune responses, and how to improve vaccine design in this age group is lacking. Restimulating preexisting memory T cells against conserved epitopes in influenza virus by a vaccine might confer protective immunity in this age group. An ideal vaccine for elderly should therefore engage pattern recognition receptors (PRRs) that activate antigen-presenting cells (APCs), generate conserved antigenic epitopes, while avoiding overt inflammatory responses. In Phase I, we showed that M2SR virus results in robust restimulation of memory CD4 and CD8 T cells in older humans without causing pathological inflammation by engaging non-inflammasome dependent innate pathways. In this Phase II proposal, we will explore how M2SR stimulates antiviral immune responses in older subjects in the following aims: Aim 1. Examine dendritic cell survival and function in response to M2SR infection. Aim 2: Determine the molecular mechanism of interferon stimulated gene expression regulation in dendritic cells. Aim 3: Evaluate the early immune response in human subjects vaccinated with M2SR. These experiments are aimed at improving protection of older humans from influenza-mediated disease, by understanding the fundamental innate immune defects that contribute to failure to mount protective immunity. The outcome of the experiments is expected to have high impact, both with respect to the fundamental understanding of the underlying mechanism of flu-related illnesses in the susceptible elderly population, and in providing a basis with which to design vaccine and immunotherapeutic interventions.