A revised model for immune imprinting by influenza virus

项目摘要 流感病毒的免疫印记被描述为免疫记忆的终身偏差， 预防儿童早期遇到的流感病毒株。它已成为越来越多的焦点， 流感研究领域。免疫印迹被认为反映了与早期免疫相关的独特事件。 生命感染，主要被视为B细胞记忆的功能。在本提案中，我们将测试许多 那些被认为是最早期感染的发现事实上可以在很大程度上解释 通过涉及首次感染期间发生的CD4 T细胞特异性和功能性的替代机制， 这会影响对此后发生的所有流感感染的反应。 我们将通过一系列的实验来检验所提出的模型，该模型是从我们积累的大量研究中得出的 其目标是确定是否建立具有排他性和选择性肺的预先存在的免疫力， 启动的CD4 T细胞引发，随后是病毒感染攻击，将模拟免疫反应的许多特征。 印记新的分子和鼻内疫苗策略将用于选择性地引发呼吸道感染。 通过递送到呼吸道中，将所选择的流感表位递送到呼吸道和CD4 T细胞区室中。我们将 测试是否引发亚型特异性HA CD4 T细胞应答和对表位特异的CD4 T细胞， A型流感亚型之间的保守性可以在CD4 T细胞中的偏倚方面模拟流感印迹， 以及在流感病毒攻击时发生的B细胞应答和保护。 这些问题将通过完成两个具体目标来解决： 具体目标1。推导和测试编码流感病毒-CD4肽表位的构建体，并评估 通过鼻内疫苗平台的表位特异性引发 具体目标2。检测CD4 T细胞对感染的回忆反应、抗体反应和保护作用 总的来说，这些实验的完成有可能从根本上改变我们对 被认为是人类对流感的保护性免疫的重大障碍， 策略，以克服在主机的缺陷，导致有害影响的印记。

PROJECT SUMMARY Immune imprinting by influenza virus has been described as a lifelong bias in immune memory of, and protection against, influenza strains encountered in early childhood. It has become an increasing focus in the field of influenza research. Immune imprinting has been thought to reflect unique events associated with early life infections and is viewed primarily as a function of B cell memory. In this proposal, we will test that many of the findings that have been attributed to the earliest infections can in fact be explained to a significant degree by an alternate mechanism involving CD4 T cell specificity and functionality that occurs during the first infection and that biases the responses to all influenza infections that occur thereafter. The proposed model, drawn from much of our accumulated research, will be tested by a series of experiments whose goal is to determine whether establishing pre-existing immunity with exclusive and selective lung- initiated CD4 T cell priming, followed by virus infection challenge, will mimic many of the features of immune imprinting. Novel molecular and intranasal vaccine strategies will be used to selectively prime the respiratory tract and CD4 T cell compartment for selected influenza epitopes by delivery into the respiratory tract. We will test whether priming subtype-specific HA CD4 T cell responses and CD4 T cells specific for epitopes that are conserved across influenza A subtypes can mimic influenza imprinting with regard to the biases in CD4 T cell and B cell responses and protection that occur upon influenza virus challenge. These issues will be addressed through completion of two Specific Aims: Specific Aim 1. Derive and test constructs encoding influenza-CD4 peptide epitopes and evaluate epitope specific priming via intranasal vaccine platform Specific Aim 2. Test of CD4 T recall responses to infection, antibody responses and protection Collectively, completion of these experiments have the potential to fundamentally change our understanding of what has been viewed as significant obstacle in human protective immunity to influenza and will offer strategies to overcome the deficiencies in the host that lead to the deleterious effects of imprinting.