Dissecting the receptor-mediated infection mechanisms of hantaviruses

剖析汉坦病毒受体介导的感染机制

基本信息

批准号：
9367734
负责人：
Kartik Chandran
金额：
$ 76.7万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9367734
关键词：
Affinity Americas Amino Acids Andes Virus Animal Model Animals Antiviral Agents Binding Biochemical Biological Biological Assay Biophysics Blocking Antibodies CD55 Antigens CRISPR/Cas technology Cadherins Capillary Endothelial Cell Cardiopulmonary Cell membrane Cells Crystallization Development Disease Disease Outbreaks Drug Targeting Dyes Endothelial Cells Engineering Epithelial Cells Evaluation FDA approved Frequencies Genetic Glycoproteins Goals Hamsters Hantaan virus Hantavirus Hantavirus Infections Hemorrhagic Fever with Renal Syndrome Human Individual Infection Integrin beta3 Knock-out Label Learning Lung Mediating Membrane Fusion Mesocricetus auratus Modeling Molecular Molecular Conformation Monoclonal Antibodies Mouse Strains Mus Nature Orthologous Gene Pathogenesis Population Growth Predisposition Puumala virus Reagent Resistance Rodent Roentgen Rays Role S-nitro-N-acetylpenicillamine Severities Sin Nombre virus Structure Surface Syndrome Tertiary Protein Structure Therapeutic Treatment Efficacy Tropism Vaccines Variant Viral Virion Virulence Virulent Virus Virus Diseases Virus Receptors Virus Replication Work Zoonoses base climate change design disease transmission drug development extracellular high throughput analysis in vivo live cell imaging loss of function member mutant novel protein structure receptor receptor internalization small hairpin RNA tissue tropism trafficking transmission process

项目摘要

Hantaviruses cause two disease syndromes in humans. New World agents, including Sin Nombre virus (SNV) and Andes virus (ANDV), cause a highly fatal hantavirus cardiopulmonary syndrome (HCPS) in the Americas, whereas Old World agents, including Hantaan virus (HTNV) and Puumala virus (PUUV), cause a less fatal hemorrhagic fever with renal syndrome (HFRS) in Eurasia. All known outbreaks have been traced to the zoonotic transmission of hantaviruses from their rodent host reservoirs, and human population growth and accelerating climate change may increase the frequency and size of hantavirus outbreaks in the coming decades. At present, no approved anti-hantavirus vaccines and therapeutics are available—their development is challenged by crucial gaps in our understanding of the virus-host molecular interactions that underpin infection, disease, and transmission. Current evidence indicates that human hantavirus disease arises from non-cytolytic viral infection and replication in capillary endothelial cells, and their attendant dysregulation. However, the molecular basis of endothelial cell infection, including the identities of essential receptor(s) for hantavirus entry, remains poorly understood. This proposal is centered on our recent discovery of protocadherin-1 (PCDH1), a member of the cadherin superfamily expressed in lung endothelial and epithelial cells, as a novel and critical candidate receptor for hantaviruses in endothelial cells. Our overall goals are to define the molecular mechanism by which PCDH1 mediates hantavirus entry and infection of endothelial cells; investigate the implications of this proposed virus–receptor interaction for hantavirus virulence and pathogenesis in vivo; determine its utility as a target for the development of antiviral therapeutics; and explore its potential role as a host barrier that influences hantavirus host range.

汉坦病毒在人类中引起两种疾病综合征。新世界特工，包括罪恶诺姆布雷病毒（SNV）和安第斯山脉病毒（ANDV），在美洲引起了高度致命的致命汉塔病毒心肺综合征（HCP），而旧世界特工，包括汉塔塔病毒（HTNV）和puumala病毒（puuv），导致较小的致命性血液毛血症状。所有已知的暴发都可以追溯到汉坦病毒从其啮齿动物宿主储层中的人畜共患病传播，人口增长和加速气候变化可能会增加未来几十年中汉坦病毒暴发的频率和大小。目前，尚无批准的抗汉塔病毒疫苗和治疗 - 在我们对基于感染，疾病和传播的病毒宿主分子相互作用的理解时，其发育受到关键差距的挑战。当前的证据表明，人汉塔病毒疾病是由毛细血管内皮细胞中的非溶解病毒感染和复制引起的，及其随附的失调。然而，内皮细胞感染的分子基础，包括进入汉塔病毒的必需受体的身份，仍然知之甚少。该提案集中在我们最近发现的prodocadherin-1（PCDH1）（PCDH1），这是在肺内皮和上皮细胞中表达的钙粘蛋白超家族的成员，作为一个新颖和关键的候选者，我们的总体目标是定义PCDH1介导hantavirus进入和感染的孔氏细胞的分子机制；研究该提出的病毒 - 受体相互作用对汉塔病毒病毒和体内发病机理的含义；确定其效用是开发抗病毒疗法的目标；并探索其作为影响hantavirus宿主范围的宿主屏障的潜在作用。