A revised model for immune imprinting by influenza virus

流感病毒免疫印记的修订模型

基本信息

批准号：
10630279
负责人：
Andrea Janine Sant
金额：
$ 19.75万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630279
关键词：
Address Antibody Response Antibody-mediated protection Attenuated Avian Influenza B-Lymphocytes Bypass CD4 Positive T Lymphocytes Cell Compartmentation Cells Childhood Engineering Epitopes Event Future Goals Host resistance Human Immune Immunity Immunologic Memory Immunological Models Infection Influenza Influenza A virus Life Ligands Lipoproteins Lung Memory Memory B-Lymphocyte Modeling Molecular Mus Outcome Peptides Proteins Recombinant Proteins Research Respiratory System Series T cell response T-Cell Immunologic Specificity T-Lymphocyte Epitopes Testing Vaccination Virion Virus Diseases Virus Replication early childhood experimental study flexibility imprint influenza infection influenza virus strain influenza virus vaccine influenzavirus memory CD4 T lymphocyte nano novel receptor recruit response vaccine platform vaccine strategy vector

项目摘要

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.

项目概要流感病毒的免疫印记被描述为免疫记忆的终生偏差，并且预防儿童早期遇到的流感病毒株。已经成为人们越来越关注的焦点流感研究领域。免疫印记被认为反映了与早期相关的独特事件。生命感染，主要被视为 B 细胞记忆的功能。在这个提案中，我们将测试许多事实上，归因于最早感染的发现可以在很大程度上得到解释通过涉及第一次感染期间发生的 CD4 T 细胞特异性和功能的替代机制这会导致对随后发生的所有流感感染的反应产生偏差。所提出的模型取自我们积累的大量研究成果，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力启动 CD4 T 细胞启动，然后进行病毒感染攻击，将模仿免疫的许多特征印记。新型分子和鼻内疫苗策略将用于选择性地启动呼吸道疾病通过输送到呼吸道中来选择流感表位的呼吸道和 CD4 T 细胞区室。我们将测试是否引发亚型特异性 HA CD4 T 细胞反应和对表位具有特异性的 CD4 T 细胞在甲型流感亚型中保守的 CD4 T 细胞偏差可以模拟流感印记流感病毒攻击时发生的 B 细胞反应和保护。这些问题将通过完成两个具体目标来解决：具体目标 1. 推导并测试编码流感 CD4 肽表位的构建体并评估通过鼻内疫苗平台进行表位特异性引发具体目标 2. 测试 CD4 T 对感染的回忆反应、抗体反应和保护总的来说，完成这些实验有可能从根本上改变我们对这被认为是人类对流感的保护性免疫力的重大障碍，并将提供克服宿主缺陷导致印记有害影响的策略。