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

• 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
• 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

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.

项目概要 中东呼吸综合征冠状病毒（MERS-CoV）是一种人畜共患病毒 这可能会导致患有潜在合并症的患者患上致命疾病。更远 对这种呼吸综合征的认识和预防策略需要少量的努力 动物感染模型以及对病毒的进一步了解。这个PPG 描述了中东呼吸综合征冠状病毒疾病的小鼠模型。在这个模型中，病毒引起 该疾病是适应变种，专门针对小鼠肺部感染。相比之下，非 适应的中东呼吸综合征冠状病毒会引起小鼠感染，但不会引起疾病。这 该子项目（PPG2）的中心假设是，适应小鼠的变体可以 通过非适应者无法利用的途径有效进入宿主细胞 病毒。为了解决这一假设，将构建重组中东呼吸综合征冠状病毒并 评估以确定细胞进入介导中是否存在小鼠适应性突变 病毒刺突蛋白与有效的小鼠肺部感染相关。替代中东呼吸综合征冠状病毒 将构建和评估伪病毒，以解决以下重点假设： 小鼠适应变体介导“早期”质膜细胞进入，即 对于非适应性病毒不可用。该项目将剖析峰值的机制 蛋白质介导通过质膜的早期细胞进入与晚期细胞进入 通过内体。选择早期与晚期细胞进入的基础是 通过识别促进或限制任一途径的宿主细胞因子来确定。这 项目还将确定适当的抗病毒策略，通过预防早期 和晚期病毒进入细胞。所有这些目标的基本原理是额外的 了解 MERS-CoV 细胞进入途径将确定稳健的相关性 感染和疾病，还将提供有关预防感染的最佳方法的见解 和疾病与创新的病毒进入抑制剂。