A revised model for immune imprinting by influenza virus

项目总结 流感病毒的免疫印记被描述为对免疫记忆的终生偏见，以及 对儿童早期遇到的流感病毒株的保护。它已经成为世界上日益关注的焦点 流感研究领域。免疫印记一直被认为反映了与早期 生命感染，主要被视为B细胞记忆的一种功能。在本提案中，我们将测试许多 这些发现归因于最早的感染，实际上可以在很大程度上解释 通过第一次感染期间发生的涉及CD4T细胞特异性和功能的另一种机制 这就偏向了对之后发生的所有流感感染的反应。 提出的模型来自我们积累的大量研究，将通过一系列实验进行测试 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- 最初的CD4T细胞启动，随后是病毒感染的挑战，将模仿免疫的许多特征 印记。新的分子和鼻腔疫苗策略将被用于选择性地启动呼吸道 通过将选定的流感表位送入呼吸道，通过肠道和CD4T细胞隔间进行识别。我们会 测试是否启动亚型特异性HA CD4T细胞反应和CD4T细胞特异性表位 在甲型流感亚型中保守可以模仿流感印记在CD4T细胞中的偏向 和B细胞在流感病毒攻击时的反应和保护。 这些问题将通过完成两个具体目标来解决： 具体目标1.获得和测试编码流感-CD4多肽表位的构建体并进行评估 通过鼻腔疫苗平台进行表位特异性引爆 特定目标2.检测CD4T细胞对感染的召回反应、抗体反应和保护 总的来说，这些实验的完成有可能从根本上改变我们对 被视为人类对流感的保护性免疫的重大障碍，并将提供 克服宿主中导致印记有害影响的缺陷的策略。

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.