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，老年人和免疫功能低下的个体。目前没有许可的RSV疫苗。 RSV特定的高滴度抗体可以提供针对严重RSV诱导疾病的保护；但是，即使是最高的抗体滴度无法保护某些人免受RSV的再感染和疾病的侵害。因此，保护性的相关性对RSV的免疫力尚不清楚。记忆CD8 T细胞可以为宽阔的保护性提供保护性免疫急性病毒感染的范围，包括呼吸道病毒，例如流感病毒和严重的急性呼吸综合征（SARS）人冠状病毒。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重大损害。因为很明显抗体单独不足以提供针对RSV感染的完全保护，我们假设诱导在没有RSV特异性内存CD4 T的情况下细胞和抗体将对RSV感染提供保护性免疫。为了测试我们假设我们修改了一种加速的素数/增强方法，以生成可靠的预先存在的内存CD8 T 特定于免疫主导M282-90表位的细胞种群。我们的初步数据表明RSV- 特定的内存CD8 T细胞可以显着抑制病毒复制，但出乎意料地以成本为代价在RSV挑战中引起致命的免疫病理学。重要的是，免疫病理学不是固有的 T细胞的特性，因为RSV特异性内存CD8 T细胞能够介导保护而无需反对致命挑战的免疫病理学，具有表达RSV衍生的重组流感病毒 M282-90表位。我们的数据表明，严格的基于T细胞的RSV疫苗的设计可能会严重结果。因此，关于RSV特异性内存CD8 T细胞的重要知识差距控制RSV感染的功能以及导致免疫病理发展的机制。这该建议的目标是解决这些关键的知识差距，并提供机械洞察力可以操纵CD8 T细胞以赋予RSV感染的最佳保护性免疫。我们将实现通过追求以下三个特定目标：目标1。确定记忆机制CD8 T的机制 RSV感染后细胞介导的免疫病理学。目标2。调查记忆的特征在RSV挑战后增强免疫力并限制免疫病理学的CD8 T细胞。目标3。定义防止RSV感染的最佳保护相关性。从这些研究中获得的知识将提供有关保护性免疫与RSV相关的重要信息，这些信息将极大地影响未来RSV疫苗候选物的设计和评估。呢