Filoviral glycoprotein/cellular protein interactions

丝状病毒糖蛋白/细胞蛋白相互作用

基本信息

批准号：
8260870
负责人：
Wendy Jean Maury
金额：
$ 28.3万
依托单位：
UNIVERSITY OF IOWA
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：
2010-05-18 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8260870
关键词：
Africa Antibodies Antigens Antiviral Agents Antiviral Therapy Apical Autopsy Binding Bioinformatics Body Weight decreased CD4 Positive T Lymphocytes Categories Cell Line Cell Surface Receptors Cell surface Cells Comparative Genomic Analysis Complement Cytoplasmic Tail Democratic Republic of the Congo Development Disease Outbreaks Drug or chemical Tissue Distribution Ebola virus Ectopic Expression Endothelial Cells Epithelial Cells Epithelium Family member Filovirus Frankfurt-Marburg Syndrome Virus Future Galactosidase Genes Glycoproteins Helper-Inducer T-Lymphocyte Human Immunoglobulins Immunohistochemistry In Situ Hybridization Infection Iowa Kidney Knock-in Mouse Knock-out Knockout Mice Knowledge Lead Masks Mediating Membrane Proteins Morbidity - disease rate Mucin 1 protein Mucins Mus Pathogenesis Pattern Population Proteins Reporting Respiratory System Respiratory tract structure Role Screening procedure Structure of respiratory epithelium Surface T-Lymphocyte Testing Tissues Tyrosine United States National Institutes of Health Universities Vaccines Viral Hemorrhagic Fevers Viremia Virus Virus Diseases Virus-Cell Membrane Interaction Zoonotic Infection base biodefense design hepatoma cell in vivo mortality mouse model novel public health relevance receptor receptor binding transduction efficiency transmission process uptake virus pathogenesis

项目摘要

DESCRIPTION (provided by applicant): The filoviruses Ebola (EBOV) virus and Marburg (MARV) virus are responsible for devastating hemorrhagic fever outbreaks. No vaccines or therapies are currently available against these agents. Because of the high morbidity and mortality associated with infection, these zoonotic viruses have been placed on the NIH Biodefense Category A list. A cellular receptor that binds to and mediates filovirus uptake has not been identified. Identification of such a receptor and elucidation of filoviral glycoprotein (GP)/receptor interactions will facilitate the development of antivirals and enhance knowledge of filoviral pathogenesis. This submission is designed to help fill this knowledge gap. We have identified that the surface protein TIM-1 serves as a cellular receptor for filoviruses on epithelial cells. These studies will elucidate the interactions between human and murine TIM-1 and filovirus glycoproteins that are required for binding and virus entry into endothelial cells. Additionally, our studies to date demonstrated that the expression of TIM-1 within the body is poorly understood. In tissue sections, we will identify cells that express TIM-1 hypothesizing that TIM-1 expression is common on many epithelia. Finally, using a tim-1 knock out mouse, we will determine the impact of Tim-1 on EBOV infection and pathogenesis in the mouse model. In total, these studies will pave the way for the development of future antivirals against these deadly viruses. PUBLIC HEALTH RELEVANCE: Outbreaks in Africa of the filoviruses, Ebola virus and Marburg virus, are sporadic and unpredictable with these deadly infections having mortality rates as high as 90% with no current vaccines or antiviral treatments available. Here, we identify that the cellular protein TIM-1 is a receptor for both Ebola and Marburg virus and seek to understand the molecular interactions between TIM-1 and filovirus glycoproteins that lead to virus infection. Further, studies will be performed to understand the role of TIM-1 in Ebola virus pathogenesis for a better understanding of cellular proteins that mediate filovirus binding and entry into cells that will facilitate the development of antiviral therapies potentially curbing transmission and infection.

描述（由申请人提供）：埃博拉病毒（EBOV）病毒和马堡病毒（MARV）病毒负责毁灭性的出血热暴发。目前没有针对这些药剂的疫苗或疗法。由于与感染相关的发病率和死亡率很高，因此将这些人畜共患病毒置于NIH Biodefense A类列表中。尚未鉴定与结合并介导的fialoviat病毒摄取并介导的细胞受体。这种受体的鉴定并阐明了丝状病毒糖蛋白（GP）/受体相互作用，将有助于抗病毒药物的发育并增强对丝病毒发病机理的了解。此提交旨在帮助填补这一知识差距。我们已经确定表面蛋白TIM-1用作上皮细胞上丝状病毒的细胞受体。这些研究将阐明人与鼠TIM-1和丝状病毒糖蛋白之间的相互作用，这些相互作用是结合和病毒进入内皮细胞所需的。此外，迄今为止，我们的研究表明，人体内部TIM-1的表达知之甚少。在组织切片中，我们将鉴定出表达TIM-1的细胞，假设TIM-1表达在许多上皮上很常见。最后，使用TIM-1敲除小鼠，我们将确定TIM-1对EBOV感染和小鼠模型发病机理的影响。总的来说，这些研究将为对这些致命病毒的未来抗病毒药的发展铺平道路。公共卫生相关性：非洲疫苗病毒，埃博拉病毒和马尔堡病毒的爆发是零星且无法预测的，这些致命感染的死亡率高达90％，没有当前的疫苗或抗病毒药物。在这里，我们确定细胞蛋白TIM-1是埃博拉病毒和马堡病毒的受体，并试图理解TIM-1和丝状病毒糖蛋白之间导致病毒感染的分子相互作用。此外，将进行研究，以了解TIM-1在埃博拉病毒发病机理中的作用，以更好地理解介导丝状病毒结合并进入细胞的细胞蛋白，从而促进抗病毒疗法的发展潜在地抑制传播和感染。