Balancing protection versus immunopathology by RSV-specific memory CD8 T cells

RSV 特异性记忆 CD8 T 细胞平衡保护与免疫病理学

基本信息

批准号：
9977905
负责人：
Steven M Varga
金额：
$ 37.69万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9977905
关键词：
Acute Address Animal Model Antibodies Antibody titer measurement CD8-Positive T-Lymphocytes Cell physiology Characteristics Child Data Development Disease Elderly Epitopes Equilibrium Ethics Evaluation Future Goals Human Immunity Immunization Immunocompromised Host Individual Knowledge Lower Respiratory Tract Infection Lung diseases Mediating Memory Mission Morbidity - disease rate Pathology Population Property Public Health Reagent Recombinants Research Respiratory Syncytial Virus Infections Respiratory Syncytial Virus Vaccines Respiratory syncytial virus Severe Acute Respiratory Syndrome Structure of parenchyma of lung T cell response T memory cell T-Lymphocyte Target Populations Testing United States United States National Institutes of Health Vaccinated Vaccination Vaccine Design Viral Viral Load result Virus Virus Diseases Virus Replication base burden of illness cost design human coronavirus immunopathology influenzavirus insight memory CD4 T lymphocyte mortality mouse model novel therapeutic intervention novel vaccines respiratory virus vaccine candidate virus infection mechanism

项目摘要

ABSTRACT Respiratory syncytial virus (RSV) is a leading cause of severe respiratory disease in children, the elderly and immunocompromised individuals. There is currently no licensed RSV vaccine. High titers of RSV-specific antibodies can provide protection against severe RSV-induced disease; however, even the highest antibody titers fail to protect some individuals against RSV reinfection and disease. Thus, the correlates of protective immunity against RSV remain unclear. Memory CD8 T cells can provide protective immunity against a wide range of acute viral infections, including respiratory viruses such as influenza virus and the severe acute respiratory syndrome (SARS) human coronavirus. In most virus infections, memory CD8 T cells mediate viral clearance without causing substantial damage to the infected host. Because it is clear that antibodies alone are not sufficient to provide complete protection against RSV infection, we hypothesized that induction of a strong pre-existing RSV-specific memory CD8 T cell response in the absence of RSV-specific memory CD4 T cells and antibodies would provide protective immunity against an RSV infection. In order to test our hypothesis we modified an accelerated prime/boost approach to generate robust pre-existing memory CD8 T cell populations specific to the immunodominant M282-90 epitope. Our preliminary data indicate that RSV- specific memory CD8 T cells can significantly inhibit viral replication, but unexpectedly do so at the cost of causing fatal immunopathology upon RSV challenge. Importantly, the immunopathology was not an inherent property of the T cells, as RSV-specific memory CD8 T cells were capable of mediating protection without immunopathology against a lethal challenge with a recombinant influenza virus expressing the RSV-derived M282-90 epitope. Our data reveal that the design of a strictly T cell-based RSV vaccine could have severe consequences. Thus, important knowledge gaps exist regarding how RSV-specific memory CD8 T cells function to control RSV infection and the mechanisms that result in the development of immunopathology. The goal of this proposal is to address these critical knowledge gaps and provide mechanistic insight into if memory CD8 T cells can be manipulated to confer optimal protective immunity against RSV infection. We will achieve these goals by pursuing the following three specific aims: Aim 1. Determine the mechanism of memory CD8 T cell-mediated immunopathology following RSV infection. Aim 2. Investigate the characteristics of memory CD8 T cells that enhance immunity and limit immunopathology after RSV challenge. Aim 3. Define the optimal correlates of protection against RSV infection. The knowledge gained from these studies will provide vital information regarding the correlates of protective immunity to RSV, information that will greatly impact the design and evaluation of future RSV vaccine candidates. !

抽象的呼吸道合胞病毒（RSV）是儿童、老年人和儿童严重呼吸道疾病的主要原因。免疫功能低下的个体。目前尚无获得许可的 RSV 疫苗。 RSV 特异性高滴度抗体可以针对严重 RSV 诱发的疾病提供保护；然而，即使是最高的抗体滴度无法保护某些个体免受 RSV 再次感染和疾病。因此，保护的相关性针对 RSV 的免疫力仍不清楚。记忆 CD8 T 细胞可以提供针对多种疾病的保护性免疫一系列急性病毒感染，包括流感病毒等呼吸道病毒和严重急性病毒感染呼吸综合征（SARS）人类冠状病毒。在大多数病毒感染中，记忆 CD8 T 细胞介导病毒清除而不会对受感染的宿主造成实质性损害。因为很明显，仅抗体不足以提供针对 RSV 感染的完全保护，我们假设诱导在缺乏 RSV 特异性记忆 CD4 T 的情况下，预先存在的强烈 RSV 特异性记忆 CD8 T 细胞反应细胞和抗体将提供针对 RSV 感染的保护性免疫力。为了测试我们的假设我们修改了加速的prime/boost方法来生成强大的预先存在的内存CD8 T 对免疫显性 M282-90 表位具有特异性的细胞群。我们的初步数据表明 RSV- 特异性记忆CD8 T细胞可以显着抑制病毒复制，但出人意料的是这样做的代价是 RSV 攻击后引起致命的免疫病理学。重要的是，免疫病理学并不是固有的。 T 细胞的特性，因为 RSV 特异性记忆 CD8 T 细胞能够介导保护，而无需针对表达 RSV 衍生的重组流感病毒致命攻击的免疫病理学 M282-90表位。我们的数据表明，严格基于 T 细胞的 RSV 疫苗的设计可能会产生严重的影响。结果。因此，关于 RSV 特异性记忆 CD8 T 细胞如何控制 RSV 感染的功能以及导致免疫病理学发展的机制。这该提案的目标是解决这些关键的知识差距，并提供对记忆的机械洞察 CD8 T 细胞可以被操纵以赋予针对 RSV 感染的最佳保护性免疫力。我们将实现通过追求以下三个具体目标来实现这些目标：目标 1. 确定记忆 CD8 T 的机制 RSV 感染后的细胞介导的免疫病理学。目标 2. 研究记忆的特征 CD8 T 细胞在 RSV 攻击后增强免疫力并限制免疫病理。目标 3. 定义 RSV 感染保护的最佳相关性。从这些研究中获得的知识将提供有关 RSV 保护性免疫相关性的重要信息，这些信息将极大地影响未来 RSV 候选疫苗的设计和评估。！