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：
10203768
负责人：
Kartik Chandran
金额：
$ 41.26万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10203768
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 ITGB3 gene Individual Infection 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，包括辛诺布尔病毒（SNV）和安第斯病毒（ANDV），在美洲引起高度致命的汉坦病毒心肺综合征（HCPS），而旧世界病毒，包括汉坦病毒（HTNV）。 ) ) 和普马拉病毒 (PUUV) 在欧亚大陆引起一种不太致命的肾综合征出血热 (HFRS) 所有已知的疫情都可追溯到人畜共患病传播。啮齿动物宿主宿主中的汉坦病毒、人口增长和气候变化加速可能会增加未来几十年汉坦病毒爆发的频率和规模。目前，还没有获得批准的抗汉坦病毒疫苗和治疗方法——它们的开发面临着重大差距的挑战。在我们对支持感染、疾病和传播的病毒-宿主分子相互作用的理解中，目前的证据表明，人类汉坦病毒病是由毛细血管内皮细胞中的非溶细胞性病毒感染和复制及其伴随现象引起的。然而，内皮细胞感染的分子基础，包括汉坦病毒进入的必需受体的身份，仍然知之甚少。该提议的重点是我们最近发现的钙粘蛋白成员原钙粘蛋白-1 (PCDH1)。超家族在肺内皮和上皮细胞中表达，作为内皮细胞中汉坦病毒的新型关键候选受体，我们的总体目标是确定 PCDH1 介导的分子机制。汉坦病毒进入和感染内皮细胞；研究这种拟议的病毒-受体相互作用对汉坦病毒毒力和体内发病机制的影响；确定其作为抗病毒疗法开发的靶标的效用，并探索其作为影响宿主屏障的潜在作用；汉坦病毒宿主范围。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

MAVERICC: Marker-free Vaccinia Virus Engineering of Recombinants through in vitro CRISPR/Cas9 Cleavage.

DOI：
10.1016/j.jmb.2021.166896
发表时间：
2021-04-30
期刊：
Journal of molecular biology
影响因子：
5.6
作者：
Laudermilch E;Chandran K
通讯作者：
Chandran K

The Hantavirus Surface Glycoprotein Lattice and Its Fusion Control Mechanism.

DOI：
10.1016/j.cell.2020.08.023
发表时间：
2020-10-15
期刊：
Cell
影响因子：
64.5
作者：
Serris A;Stass R;Bignon EA;Muena NA;Manuguerra JC;Jangra RK;Li S;Chandran K;Tischler ND;Huiskonen JT;Rey FA;Guardado-Calvo P
通讯作者：
Guardado-Calvo P

Vesicular Stomatitis Virus-Based Vaccines Provide Cross-Protection against Andes and Sin Nombre Viruses.

水疱性口炎病毒疫苗可针对安第斯山脉病毒和辛诺布病毒提供交叉保护。

DOI：
10.3390/v11070645
发表时间：
2019
期刊：
Viruses
影响因子：
0
作者：
Warner,BryceM;Stein,DerekR;Jangra,RohitK;Slough,MeganM;Sroga,Patrycja;Sloan,Angela;Frost,KathyL;Booth,Stephanie;Chandran,Kartik;Safronetz,David
通讯作者：
Safronetz,David