Nipah Virus Pathobiology and Effects on Innate Immunity

尼帕病毒病理学及其对先天免疫的影响

基本信息

批准号：
7214116
负责人：
Linda G Baum
金额：
$ 36.62万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-03-15 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7214116
关键词：
Address Agricultural Workers Agriculture Antigens Antiviral Agents Area Automobile Driving Autopsy Bangladesh Binding Biological Assay Biology Canada Carbohydrates Categories Cell Line Cell fusion Cell physiology Cell surface Cells Cellular Membrane Codon Nucleotides Collaborations Data Set Dendritic Cells Development Disease Outbreaks Encephalitis Endothelial Cells Ensure Funding Future GTP-Binding Proteins Galactose Binding Lectin Galectin 1 Giant Cells Glues Glycobiology Glycoproteins Grant Health Henipavirus Human Immune Immune response Immune system Immunology Infection Infectious Diseases Research Inflammation Inflammatory Interferons Lectin Life Livestock Lymphoid Tissue Malaysia Mediating Mediation Mediator of activation protein Membrane Fusion Membrane Microdomains Mutagenesis National Institute of Allergy and Infectious Disease National Institute of General Medical Sciences Natural Immunity Nipah Virus Numbers Oligosaccharides Paramyxoviridae Paramyxovirus Pathogenesis Pathologic Pathologist Patients Play Polysaccharides Principal Investigator Process Production Rate Reagent Receptor Cell Research Research Personnel Role Singapore Structure T-Lymphocyte Testing Therapeutic Time Tissues Tropism Viral Virus Virus Diseases Virus Receptors Work base biodefense biosafety level 4 facility cell type cytokine env Glycoproteins experience glycoprotein G glycosylation in vivo inhibitor/antagonist innovation interdisciplinary approach lymph nodes member monocyte mortality mutant novel novel strategies particle pathogen receptor response virology virus envelope virus pathogenesis

项目摘要

The Nipah virus (NiV) is an emerging viral pathogen, classified as a Category C pathogen of the NIAID Biodefense Research Agenda. NiV infects agricultural livestock and humans; in 1999, NiV infection among agricultural workers in Malaysia and Singapore resulted in a 40% mortality rate and loss of livestock worth over $100 million. NiV is a member of a new genus of paramyxoviruses, and little is known about NiV biology or the immune response to NiV. However, autopsy studies of NiV victims found that the virus targets lymph nodes and endothelial cells with endothelial syncytia formation being the pathologic hallmark of NiV infection. Cell fusion and syncytia formation depend on expression of the NiV F and G envelope glycoproteins. We have found that syncytia formation is regulated by glycosylation of these envelope glycoproteins, with specific N-glycans on NiV F and G playing important roles in cell fusion. Importantly, we have also found that cell fusion can be blocked by galectin-1, an endogenous lectin of the innate immune system that is expressed by endothelial cells and dendritic cells. In addition, we have made the novel observation that galectin-1 induces robust pro-inflammatory cytokine secretion by monocyte derived dendritic cells, an effect that may augment an antiviral immune response. Our driving hypothesis for this proposal is that glycan structures on the NiV F and G glycoproteins. and the innate immune lectin galectin-1 that recognizes these structures, are critical determinants in the pathogenesis of this viral disease. Our Specific Aims are: (1) Determine structural features of oligosaccharides on the F and G env glycoproteins that are critical for glycoprotein expression and syncytia formation, (2) Elucidate the mechanism by which galectin-1 regulates NiV envelope glycoprotein-mediated cell fusion, (3) Characterize the structural features involved in binding to and fusion of target cells, (4) Examine the effects of galectin-1 on soluble mediators of the innate and adaptive immune response. This work will address critical issues for rapid development of strategies to enhance innate immune responses to this emerging viral pathogen. The co-investigators have a unique combination of expertise, and propose an innovative set of studies into the glycobiology of NiV pathogenesis.

NIPAH病毒（NIV）是一种新兴的病毒病原体，被归类为Niaid Biodefense研究议程的C类病原体。 NIV感染农业牲畜和人类； 1999年，马来西亚和新加坡农业工人之间的NIV感染导致40％的死亡率和牲畜损失，价值超过1亿美元。 NIV是帕托病毒新属的成员，对NIV生物学或对NIV的免疫反应知之甚少。然而，对NIV受害者的尸检研究发现，该病毒靶向淋巴结和内皮细胞，内皮合胞菌的形成是NIV感染的病理标志。细胞融合和合胞体的形成取决于NIV F和G包膜糖蛋白的表达。我们发现，合成曲霉的形成受这些包膜糖蛋白的糖基化调节，NIV F和G上的特定N-聚糖在细胞中起重要作用融合。重要的是，我们还发现细胞融合可以被galectin-1（一种由天生免疫系统的内源性凝集素）阻塞，该系统由内皮细胞和树突状细胞表达。此外，我们已经做出了新的观察结果，即galectin-1通过单核细胞衍生的树突状细胞诱导鲁棒的促炎细胞因子分泌，这种作用可能会增强抗病毒免疫反应。我们对该提案的驾驶假设是NIV F和G糖蛋白上的聚糖结构。识别这些结构的先天免疫凝集素galectin-1是这种病毒疾病发病机理中的关键决定因素。我们的具体目的是：（1）确定对F和G Env糖蛋白上寡糖的结构特征，这对于糖蛋白表达和合成蛋白的形成至关重要，（（2）阐明Galectin-1调节Niv eniv glamcopople蛋白介导的细胞融合的机制，（3）（4）表征与靶细胞结合和融合涉及的结构特征，（4）检查lectectin-1对先天性和适应性免疫反应的可溶性介体的影响。这项工作将解决快速发展策略以增强对这种新兴病毒病原体的先天免疫反应的关键问题。共同投资者具有独特的专业知识组合，并提出了对NIV发病机理糖生物学的创新研究。