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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

基本信息

批准号：
8389669
负责人：
J. Lindsay Whitton
金额：
$ 43.74万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-01-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8389669
关键词：
Acute Acute Disease Adult Affect Age Agonist Animal Model Antibodies Antigen Presentation Antigens Applications Grants Back Belief Biological Biological Assay Bone Marrow Bone Marrow Cells Bone Marrow Stem Cell CD4 Positive T Lymphocytes CD8B1 gene Cardiac Cell Count Cell Cycle Cells Cessation of life Child Chronic Color Complement Coxsackie Viruses Data Data Set Defect Detection Deterioration Development Disease DsRed Electronics Elements Encephalitis Enterovirus Enterovirus Infections Epidemiology Epitopes Etiology Exanthema Family Family Picornaviridae Female Fluorescence Microscopy Gene Expression Genome Goals Grant Harvest Health Heart Hematopoietic High Prevalence Histocompatibility Antigens Class II Histopathology Human Immune Immune response Immune system Immunity Immunocompetent Immunohistochemistry In Situ Hybridization In Vitro Individual Infant Infarction Infection Intestines Investigation Kinetics Lead Lymphocytic choriomeningitis virus Lymphoid Tissue MHC Class I Genes MHC Class II Genes Maps Marrow Measures Mediating Metabolic Methods Mind Molecular Multipotent Stem Cells Mus Myalgia Myocardial Myocardial Infarction Myocarditis Myocardium Natural History Natural Immunity Nature Neutralization Tests Newborn Infant Northern Blotting Open Reading Frames Organ Outcome Pancreatitis Pathogenesis Pathogenicity Patients Pharmaceutical Preparations Play Polyproteins Predisposition Printing Proliferating Proteins RNA RNA Viruses Reading Reagent Recombinants Reporting Research Response Elements Reverse Transcriptase Polymerase Chain Reaction Role Science Series Sex Characteristics Site Sorting - Cell Movement Source Specific qualifier value Spleen Stem cell transplant Stem cells Symptoms System T cell response T-Lymphocyte Testing Time Tissues Toll-like receptors Transgenic Organisms Translating Transplantation Trauma United States National Institutes of Health Vaccines Viral Virus Virus Diseases Western Blotting Work age group base bone cell type disability helicase human disease human morbidity human mortality in vivo interest lymph nodes male neonate novel novel strategies pathogen polypeptide prevent repaired repository respiratory response sensor stem cell therapy

项目摘要

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.

柯萨奇病毒B3会引起心肌炎、胰腺炎和脑膜脑炎，但尽管由此导致的人类发病率和死亡率，既没有治疗方法，也没有疫苗。我的实验室有表明宿主细胞的代谢状态在决定CVB3的结果中起着关键作用在之前的支持阶段，我们将干细胞确定为CVB3的早期靶点感染。在本次续费申请中，我提出了4个具体目标，重点围绕以下主题： 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~1%的骨髓细胞。我们将对骨髓进行鉴定和鉴定被感染的细胞；并将评估这种感染的生物学影响。 2.我们将确定细胞激活在调节心脏中CVB3感染中的作用。我们会用各种方法问：增殖细胞是目标细胞吗？心肌干细胞是首选吗？感染的地方？先前的心肌损伤是否会改变心脏中的病毒复制，并做到这一点加重病毒性心肌炎？ 3.对小核糖核酸病毒，特别是对肠道病毒的先天免疫反应是人们对此知之甚少。我们将研究淋巴组织中CVB3感染的先天反应。 (脾和淋巴结)。采取了哪些应对措施？在众多与生俱来的分子传感器中有牵连吗？先天系统的激活如何影响随后的CVB3的结果感染？ 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；也不会在wtCVB3感染过程中，CD4+Nor CD8+T细胞被强烈激活。我们将使用新的方法来绘制了CVB3编码的MHC I类和II类表位的运动学和解剖学图谱，并将询问对CVB3感染的先天反应如何影响随后的发展适应性T细胞免疫。

项目成果

期刊论文数量（29）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Coxsackievirus B3 inhibits antigen presentation in vivo, exerting a profound and selective effect on the MHC class I pathway.

DOI：
10.1371/journal.ppat.1000618
发表时间：
2009-10
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Kemball CC;Harkins S;Whitmire JK;Flynn CT;Feuer R;Whitton JL
通讯作者：
Whitton JL

A novel method to establish microglia-free astrocyte cultures: comparison of matrix metalloproteinase expression profiles in pure cultures of astrocytes and microglia.

DOI：
10.1002/glia.20689
发表时间：
2008-08-15
期刊：
GLIA
影响因子：
6.2
作者：
Crocker, Stephen J.;Frausto, Ricardo F.;Whitton, J. Lindsay;Milner, Richard
通讯作者：
Milner, Richard

Preferential coxsackievirus replication in proliferating/activated cells: implications for virus tropism, persistence, and pathogenesis.

DOI：
10.1007/978-3-540-75546-3_7
发表时间：
2008
期刊：
Current topics in microbiology and immunology
影响因子：
0
作者：
R. Feuer;J. Whitton
通讯作者：
R. Feuer;J. Whitton

A novel population of myeloid cells responding to coxsackievirus infection assists in the dissemination of virus within the neonatal CNS.

DOI：
10.1523/jneurosci.1860-10.2010
发表时间：
2010-06-23
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Tabor-Godwin JM;Ruller CM;Bagalso N;An N;Pagarigan RR;Harkins S;Gilbert PE;Kiosses WB;Gude NA;Cornell CT;Doran KS;Sussman MA;Whitton JL;Feuer R
通讯作者：
Feuer R

Wild-type coxsackievirus infection dramatically alters the abundance, heterogeneity, and immunostimulatory capacity of conventional dendritic cells in vivo.