Coxsackie Myocarditis and Viral Persistence in the Heart

柯萨奇心肌炎和病毒在心脏中的持续存在

• 批准号: 7576215
• 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
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7576215
• 关键词: Acute; Adult; Affect; Agonist; Antigen Presentation; Antigens; Belief; Biological; Biological Assay; Bone Marrow; Bone Marrow Cells; CD4 Positive T Lymphocytes; CD8B1 gene; Cardiac; Cell Count; Cells; Child; Complement; Coxsackie Viruses; Data; Data Set; Defect; Detection; Development; Disease; DsRed; Elements; Encephalitis; Enterovirus; Enterovirus Infections; Epitopes; Family Picornaviridae; Fluorescence Microscopy; Gene Expression; Genome; Harvest; Heart; Hematopoietic; Histocompatibility Antigens Class II; Histopathology; Immune; Immune response; Immunity; Immunocompetent; Immunohistochemistry; In Situ Hybridization; In Vitro; Individual; Infarction; Infection; Kinetics; Lymphocytic choriomeningitis virus; Lymphoid Tissue; MHC Class I Genes; MHC Class II Genes; Maps; Marrow; Measures; Mediating; Metabolic; Methods; Molecular; Multipotent Stem Cells; Mus; Myocardial; Myocardial Infarction; Myocarditis; Myocardium; Natural Immunity; Nature; Northern Blotting; Organ; Outcome; Pancreatitis; Pharmaceutical Preparations; Play; Predisposition; Proliferating; Proteins; RNA; Research; Response Elements; Reverse Transcriptase Polymerase Chain Reaction; Role; Site; Sorting - Cell Movement; Source; Spleen; Stem cell transplant; Stem cells; System; T-Lymphocyte; Testing; Time; Tissues; Toll-like receptors; Transgenic Organisms; Transplantation; Trauma; Vaccines; Viral; Virus; Virus Diseases; Western Blotting; Work; bone; cell type; helicase; human morbidity; in vivo; interest; lymph nodes; mortality; novel; novel strategies; prevent; public health relevance; repaired; repository; response; sensor; stem cell therapy

DESCRIPTION (provided by applicant): Coxsackievirus B3 causes myocarditis, pancreatitis and meningo-encephalitis but, despite the resulting human morbidity and mortality, neither a treatment, nor a vaccine, is available. My lab has shown that the metabolic status of the host cell plays a key role in determining the outcome of CVB3 infection and, in the previous period of support, we identified stem cells as early targets of CVB3 infection. In this renewal application, I propose 4 Specific Aims, focusing on the following topics: 1. Bone marrow is the main repository of stem cells in the adult, and we show herein that CVB naturally infects ~1% of bone marrow cells in vivo. We shall identify and characterize the bone marrow cells that become infected; and will evaluate the biological implications of this infection. 2. We shall determine the role of cellular activation in regulating CVB3 infection in the heart. We shall use a variety of methods to ask: are proliferating cells targeted? Are myocardial stem cells a preferred site of infection? Does prior myocardial damage alter viral replication in the heart, and does this exacerbate the viral myocarditis? 3. The innate immune response to picornaviruses in general, and to enteroviruses in particular, is poorly understood. We shall investigate the innate responses to CVB3 infection in lymphoid tissues (spleen & lymph nodes). What responses are mounted? Which of the many innate molecular sensors are involved? How does activation of the innate system affect the outcome of subsequent CVB3 infection? 4. Many virus infections induce very strong T cell responses, but CVB3 appears not to do so; neither CD4+ nor CD8+ T cells are strongly activated during wtCVB3 infection. We shall use novel methods to map, kinetically and anatomically, the presentation of CVB3-encoded MHC class I & class II epitopes, and will ask how the innate responses to CVB3 infection affect the subsequent development of adaptive T cell immunity. 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 - especially in very young children - the diseases can be serious, and sometimes fatal. This research will help us understand how these viruses cause disease, and will provide clues about how to prevent or treat these dangerous infections.

描述(申请人提供)：柯萨奇病毒B3可引起心肌炎、胰腺炎和脑膜脑炎，但尽管导致人类发病率和死亡率，但既没有治疗方法，也没有疫苗。我的实验室已经证明，宿主细胞的代谢状态在决定CVB3感染的结局中起着关键作用，在之前的支持期间，我们确定干细胞是CVB3感染的早期靶点。在这一更新应用中，我提出了4个具体的目标，主要围绕以下主题：1.骨髓是成人干细胞的主要储存库，我们在这里证明了CVB在体内自然感染了~1%的骨髓细胞。我们将鉴定和鉴定被感染的骨髓细胞；并将评估这种感染的生物学意义。2.我们将确定细胞激活在调节心脏中CVB3感染中的作用。我们将使用各种方法来问：增殖细胞是目标细胞吗？心肌干细胞是感染的首选部位吗？先前的心肌损伤是否改变了心脏中的病毒复制，这是否加剧了病毒性心肌炎？3.一般情况下，对微小核糖核酸病毒，特别是对肠道病毒的先天免疫反应知之甚少。我们将研究淋巴组织(脾和淋巴结)对CVB3感染的先天反应。采取了哪些应对措施？在众多与生俱来的分子传感器中，有哪些与之有关？先天系统的激活如何影响后续CVB3感染的结局？4.许多病毒感染会引起非常强烈的T细胞反应，但CVB3似乎不会这样做；在wtCVB3感染期间，CD4+和CD8+T细胞都不会被强烈激活。我们将使用新的方法，从运动学和解剖学上绘制CVB3编码的MHC I类和II类表位的呈现图，并询问对CVB3感染的先天反应如何影响后续适应性T细胞免疫的发展。公共卫生相关性： 在美国，柯萨奇病毒每年感染数百万人。在大多数情况下，感染造成的伤害很小，但在某些情况下--特别是在非常年幼的儿童中--这种疾病可能很严重，有时甚至是致命的。这项研究将帮助我们了解这些病毒是如何致病的，并将为如何预防或治疗这些危险的感染提供线索。