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Norovirus Infection of Dendritic Cells and Macrophages

树突状细胞和巨噬细胞的诺如病毒感染

基本信息

批准号：
7761193
负责人：
HERBERT W VIRGIN
金额：
$ 31.4万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-15 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7761193
关键词：
Acids Address Antibodies Attenuated Australia Bacterial Gastroenteritis Binding Biology Bone Marrow COS Cells COS-7 Cell Calicivirus Capsid Capsid Proteins Carbohydrates Categories Cell Culture Techniques Cell Line Cell Surface Proteins Cell Surface Receptors Cell surface Cells Cloning Collaborations Commit Confocal Microscopy Crystallography Cytoplasm Data Dendritic Cells Development Dominant-Negative Mutation Drug usage Effectiveness Endocytosis Enteral Environment Epidemic Event Feces Funding Genes Genome Goals Grant Growth Hematopoietic Herpesviridae Human Hybridomas Image Immune Immunity Incus Infection Knowledge Laboratories Learning Letters Methods Molecular Monoclonal Antibodies Mononuclear Mus Natural Immunity Nature Norovirus Norwalk virus Paper Pathogenesis Pathway interactions Phagocytosis Plaque Assay Process Proteins Proteolysis Qualifying Queensland RNA RNA Interference Reovirus Reporting Research Research Design Role Route Science Screening procedure Structural Protein Structure Study Section System Technology Testing Transfection Tropism Universities Viral Virion Virulence Virus Virus Receptors Washington Work base cost experience expression cloning granulocyte in vivo macrophage milligram neutralizing monoclonal antibodies novel pathogen permissiveness receptor research study tissue culture tool viral RNA

项目摘要

Human noroviruses (type virus Norwalk) are the major cause of epidemic non-bacterial gastroenteritis in the world. As Category B agents, analysis of their biology is a high priority. However, these viruses have been difficult to study because they have not been cultured ex vivo. Therefore many fundamental questions remain about the biology of these viruses. In 2003 we reported the discovery of the first murine norovirus (MNV-1, Appendix 1, Karst et al., STAT1-dependent innate immunity to a Norwalk-like virus. 2003. Science. 299:1575-8). We have subsequently found that this efficient enteric virus has a surprising tropism for dendritic cells and macrophages in vivo, and used this information to develop the first tissue culture replication system for a norovirus (Appendix 2, Wobus et al., Replication of a Norovirus in cell culture reveals a tropism for dendritic cells and macrophages. PLOS Biology. E432. Epub Nov 30 2004). Using this novel system we have developed a plaque assay for MNV-1, plaque purified MNV-1, purified milligram amounts of virus, obtained the first cryo-EM image of an infectious norovirus, and proved that MNV-1 RNA is infectious, even in cells that are not permissive for MNV-1 infection. This latter result indicates that MNV-1 tropism is determined at steps in infection prior to delivery of viral RNA into the cytoplasm such as binding, entry, or uncoating. Based on these new data, there are two goals of the Specific Aims. First, we propose to define fundamental mechanisms of viral entry for a viral genus that has not been studied in detail before. Second, we seek to define whether differences in these fundamental mechanisms between cells determine MNV-1 cell tropism. The Specific Aims are: Aim 1. Define the viral events involved in MNV-1 binding, entry, and uncoating. Aim 2. Define the cellular events involved in MNV-1 binding, entry, and uncoating. Aim 3. Determine the cellular and molecular basis of MNV-1 cell tropism. The proposed studies will provide fundamental information about the binding, entry, and uncoating of a very important genus of viruses that incudes many human pathogens.

人类诺如病毒（诺瓦克型病毒）是非细菌性流行的主要原因