Adaptive MERS coronavirus-cell entry pathways and their relevance to virulence and antiviral strategies

适应性 MERS 冠状病毒细胞进入途径及其与毒力和抗病毒策略的相关性

基本信息

批准号：
10229391
负责人：
Thomas Miller Gallagher
金额：
$ 26.63万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10229391
关键词：
Acute Address Adenoviruses Adhesions Affect Animals Antiviral Agents Automobile Driving Binding Camels Cell Communication Cell Culture Techniques Cell membrane Cells Cleaved cell Coronavirus Coronavirus spike protein Dipeptidyl Peptidases Disease Disease Outbreaks Endosomes Enzymes Epidemic Evolution Exhibits Future Genes Human Infection Infection prevention Lipids Location Lung infections Measures Mediating Membrane Fusion Middle East Respiratory Syndrome Middle East Respiratory Syndrome Coronavirus Modeling Mouse Protein Mus Mutation Pathogenesis Pathway interactions Patients Peptide Hydrolases Peptides Phenotype Prevalence Prevention strategy Procedures Process Protease Inhibitor Proteins Quarantine RNA Interference Receptor Cell Recombinants Research Resistance SARS coronavirus Severe Acute Respiratory Syndrome Structure Syndrome Variant Viral Viral Proteins Virulence Virus Zoonoses adduct base cell type comorbidity coronavirus receptor human disease human pathogen improved in vivo inhibitor/antagonist innovation insight interest late endosome mouse model pressure prevent respiratory reverse genetics transmission process vaccine development vector viral transmission virology

项目摘要

PROJECT SUMMARY The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a zoonotic virus that can cause fatal disease in patients with underlying comorbidities. Further recognition of this respiratory syndrome and prevention strategies will require a small animal infection model as well as an additional understanding of the virus. This PPG describes a mouse model of MERS-CoV disease. In this model, the viruses causing disease are adapted variants, specialized for mouse lung infection. By contrast, non- adapted MERS-CoVs cause infection in the mouse but do not cause disease. The central hypothesis of this subproject (PPG2) is that mouse-adapted variants can efficiently enter host cells through pathways that are not available to the non-adapted viruses. To address this hypothesis, recombinant MERS-CoVs will be constructed and evaluated to determine whether mouse-adaptive mutations in the cell entry-mediating viral spike proteins correlate with efficient mouse lung infection. Surrogate MERS-CoV pseudo-viruses will be constructed and evaluated to address the focused hypothesis that mouse adapted variants mediate an “early” plasma-membrane cell entry that is unavailable to non-adapted viruses. The project will dissect mechanisms by which spike proteins mediate early cell entry through plasma membranes versus late cell entry through endosomes. The basis for selection of early versus late cell entry will be determined by identifying host cell factors promoting or restricting either pathway. This project will also identify appropriate antiviral strategies that operate by preventing early and late virus-cell entry. The rationale for all of these aims is that additional understanding of MERS-CoV cell entry pathways will identify correlates of robust infection and disease, and will also provide insights on the best ways to prevent infection and disease with innovative virus entry inhibitors.

项目摘要中东呼吸道综合征冠状病毒（MERS-COV）是人畜共患病毒这可能导致潜在合并症患者致命疾病。更远认识这种呼吸综合症和预防策略将需要一个小的动物感染模型以及对病毒的额外了解。这个ppg 描述了MERS-COV疾病的小鼠模型。在此模型中，引起的病毒疾病是适应变体的，专门用于小鼠肺部感染。相比之下，非改编后的MERS-COV会引起小鼠感染，但不会引起疾病。这该子标准的中心假设（PPG2）是小鼠适应的变体可以有效地通过未适应的途径进入宿主单元病毒。为了解决这一假设，将构建重组MERS-COV，并评估以确定小鼠自适应突变是否在细胞进入中间病毒尖峰蛋白与有效的小鼠肺部感染相关。代理MERS-COV 伪病毒将进行构建和评估，以解决以下集中的假设，即鼠标改编的变体介导了一个“早期”等离子体 - 膜细胞输入非适应性病毒无法获得。该项目将剖析尖峰的机制蛋白质通过质膜与晚期细胞进入介导早期细胞进入通过内体。选择早期和晚细胞进入的基础是通过识别促进或限制这两种途径的宿主细胞因子来确定。这项目还将确定通过预防早期来运行的适当抗病毒策略和晚病细胞进入。所有这些目标的理由是了解MERS-COV细胞进入途径将确定鲁棒的相关性感染和疾病，还将提供有关防止感染的最佳方法的见解和具有创新病毒进入抑制剂的疾病。