Innate and Adaptive Immune Responses in the Virus-Infected Heart

病毒感染心脏的先天性和适应性免疫反应

基本信息

批准号：
7886341
负责人：
J. Lindsay Whitton
金额：
$ 47.48万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7886341
关键词：
Ablation Acute Acute Disease Acute Myocarditis Address Adenoviruses Affect Agreement Animals Anthracyclines Antigen Presentation Antigens Antiviral Agents Applications Grants Autoimmunity Bacteria Biological Assay Brefeldin A CD22 antigen CD4 Positive T Lymphocytes CD8B1 gene Camping Candida Cardiac Cardiac Myocytes Cardiovascular system Cell physiology Cessation of life Chronic Classification Clinical Cocaine Color Confocal Microscopy Coxsackie B Viruses Coxsackie Viruses Data Development Diagnosis Dilated Cardiomyopathy Dimensions Disease Echo Viruses Electronics Enterovirus Epitopes Equilibrium Evolution Exanthema Excision Family Family Picornaviridae Frequencies Gene Expression Genome Goals Grouping HIV Heart Heart Diseases Hepatitis C virus Home environment Homing Human Human poliovirus Immune Immune response Immune system Immunity In Situ Hybridization Incidence Infection Infection Control Infectious Agent Infiltration Inflammation Injury Intake Interferon Receptor Interferon Type I Interferons Kinetics Knock-out Knowledge Laboratories Lead Logic Maintenance Maps Measures Modeling Mouse Strains Mus Myalgia Myocardial Myocarditis Myocardium Names Nature Open Reading Frames Organ Organism Outcome Pancreas Parasites Parvovirus Pathology Peptide/MHC Complex Pharmaceutical Preparations Phase Phenotype Plaque Assay Play Polioviruses Polyproteins Printing Production Proteins Protozoa Publishing RNA RNA Viruses Reading Reagent Receptor Signaling Recombinants Recrudescences Reporting Research Research Design Resolution Role Sarcoidosis Schistosoma Science Signal Transduction Signs and Symptoms Slice Staining method Stains Streptococcus Symptoms System T cell response T-Cell Immunologic Specificity T-Cell Receptor T-Lymphocyte T-Lymphocyte Epitopes Techniques Therapeutic Thyrotoxicosis Time Tissues Transgenic Organisms Translating Trypanosoma cruzi Viral Viral Antigens Viral Load result Viral Proteins Virus Virus Diseases Virus Replication Work combat cytokine disability experience fungus heart cell human disease human morbidity immunopathology in vivo man member mortality mouse model neonate novel strategies polypeptide prevent prototype public health relevance receptor receptor expression recombinant virus research study respiratory response type I interferon receptor viral RNA

项目摘要

DESCRIPTION (provided by applicant): Coxsackieviruses are the commonest infectious cause of acute myocarditis, a disease that causes substantial human morbidity and mortality. Even after the virus has (apparently) been cleared, low- grade inflammation may continue, eventually leading to the serious outcome of dilated cardiomyopathy. There is general agreement that the innate and adaptive host immune responses contribute both to virus control, and to (immunopathological) heart disease. However, our knowledge of coxsackievirus-induced immune responses is rudimentary. In this proposal, using existing and new mouse models of coxsackievirus B3 (CVB3) infection, we shall evaluate the intracardiac effects of type I interferons (T1IFN) on acute and persistent CVB3 infection, and we shall use a unique set of reagents, developed in my laboratory, to assess CVB-specific T cell responses in the hearts of infected mice. There are 3 Specific Aims : 1. The effects of T1IFN in the heart are controversial. Some published work suggests that these innate cytokines may clear virus from the heart, but other work has suggested that they play no role whatsoever within the infected heart. We shall cross two existing mouse strains to develop a new mouse model in which the expression of T1IFN receptor on cardiomyocytes can be ablated at will. These mice will allow us to resolve the above controversy, and to determine if T1IFN is responsible for constraining viral spread in the acutely-infected heart. In addition, by removing this receptor during persistent infection, we shall be able to determine if T1IFN is required for the maintenance of the persistent state. 2. Despite many years of study, our understanding of CVB-specific T cell responses remains minimal. To address this deficiency, my lab has generated a variety of unique reagents including recombinant CVB that expressed well-characterized CD4+ and CD8+ T cell epitopes, and genetically-marked T cells specific for those epitopes. We shall exploit our reagents to investigate the kinetics of CVB- specific CD4+ & CD8+ T cell infiltration in the heart over the course of acute myocarditis, and will determine the extent to which this T cell infiltration is regulated by T1IFN. 3. We also shall use the above reagents to map CVB3 antigen expression within the heart during acute and persistent infection. In which heart cells are antigens expressed? How quickly do antigen- specific CD4+ and CD8+ T cells home to the infected heart at various times after infection? For how long after viral clearance do epitopes remain detectable in the heart? How do virus-specific CD4+ and CD8+ T cells contribute to virus clearance, and to the development of immunopathological heart disease? PUBLIC HEALTH RELEVANCE: Coxsackieviruses infect millions of people each year in the USA. In most cases, the infections cause little harm, but in some cases the virus causes severe inflammation in the heart. This can be serious, and sometimes fatal. This research will help us understand how various parts of our immune system act inside the heart to combat this viral infection.

描述（由申请人提供）：Coxsackievievievies是急性心肌炎的最常见的感染原因，这种疾病会导致大量人类的发病率和死亡率。即使已经清除了病毒（显然），低年级炎症也可能会继续，最终导致了扩张的心肌病的严重结果。人们普遍认为，先天和适应性宿主的免疫反应既有助于控制病毒，也有助于（免疫病理）心脏病。但是，我们对Coxsackievievirus诱导的免疫反应的了解是基本的。 In this proposal, using existing and new mouse models of coxsackievirus B3 (CVB3) infection, we shall evaluate the intracardiac effects of type I interferons (T1IFN) on acute and persistent CVB3 infection, and we shall use a unique set of reagents, developed in my laboratory, to assess CVB-specific T cell responses in the hearts of infected mice.有3个具体目标：1。T1IFN在心脏中的影响是有争议的。一些发表的工作表明，这些先天的细胞因子可能会清除心脏病毒，但其他工作表明它们在感染的心脏中没有任何作用。我们应越过两种现有的小鼠菌株，以开发一种新的小鼠模型，其中T1IFN受体在心肌细胞上的表达可以随意消融。这些小鼠将使我们能够解决上述争议，并确定T1IFN是否负责抑制急性感染的心脏病毒扩散。另外，通过在持续感染期间去除该受体，我们将能够确定是否需要T1IFN来维持持续状态。 2。尽管进行了多年的研究，但我们对CVB特异性T细胞反应的理解仍然很少。为了解决这种缺陷，我的实验室生成了各种独特的试剂，包括重组CVB，表达了良好的CD4+和CD8+ T细胞表位，以及对这些表位的遗传标记的T细胞。我们应利用试剂研究在急性心肌炎过程中心脏中CVB-特异性CD4+和CD8+ T细胞浸润的动力学，并将确定T1IFN调节该T细胞浸润的程度。 3。我们还应使用上述试剂在急性和持续感染期间绘制心脏内CVB3抗原表达。在哪些心脏细胞中表达抗原？感染后的不同时间，抗原特异性CD4+和CD8+ T细胞在感染心脏中回家的速度如何？病毒清除后多长时间在心脏中仍能检测到表位？病毒特异性CD4+和CD8+ T细胞如何有助于病毒清除率，以及免疫病理心脏病的发展？公共卫生相关性：Coxsackieviruses每年在美国感染数百万人。在大多数情况下，感染很少造成伤害，但在某些情况下，病毒会引起心脏严重的炎症。这可能是严重的，有时是致命的。这项研究将有助于我们了解免疫系统的各个部位如何在心脏内部作用以抗击这种病毒感染。