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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. !

摘要