Antagonism of Coronavirus Spike Proteins by Cellular Host Factors

细胞宿主因子对冠状病毒刺突蛋白的拮抗作用

• 批准号: 10487091
• 负责人: eric freed
• 金额: $ 1.87万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10487091
• 关键词: 2019-nCoV; ATP phosphohydrolase; Address; Antiviral Agents; Binding; Binding Proteins; Biogenesis; Cell Surface Receptors; Cells; Cellular Membrane; Collaborations; Coronavirus; Coronavirus spike protein; Cryo-electron tomography; Development; E-Selectin; Endothelial Cells; Epithelial Cells; Family; Genes; Goals; HIV; HIV envelope protein; HIV-1; Human; Immune; Immune response; Infection; Innate Immune Response; Integration Host Factors; Interferon Type II; Interferons; L-Selectin; Measures; Mediating; Membrane; Membrane Glycoproteins; Middle East Respiratory Syndrome Coronavirus; National Institute of Environmental Health Sciences; Natural Immunity; P-Selectin; P-selectin ligand protein; Play; Proteins; Publishing; Role; SARS coronavirus; Structure; Surface; Tertiary Protein Structure; Therapeutic; Therapeutic Intervention; Tissues; Vaccine Design; Vaccines; Viral; Virion; Virus; Virus Diseases; Virus Replication; Virus-like particle; Work; adaptive immunity; airway epithelium; cell motility; cell type; experience; guanylate; insight; mutant; neutralizing antibody; particle; protein transport; trafficking; ubiquitin-protein ligase; viral entry inhibitor; viral transmission

In a structural and functional analysis of the SARS-CoV-2 S protein that we recently started, we have determined that MARCH8, but not a catalytically inactive MARCH8 mutant, targets the S proteins of SARS-CoV, MERS-CoV, and SARS-CoV-2 for degradation. We also showed that human airway epithelial cells express MARCH8 upon treatment with IFN. The work on MARCH protein-mediated antagonism may reveal new opportunities for therapeutic intervention with S protein trafficking and incorporation into virus particles. This work was recently published (mBio 12: e00219-21, 2021). _____In a separate study, we showed that virion incorporation of PSGL-1 on SARS-CoV and SARS-CoV-2 pseudovirions blocks S protein-mediated virus attachment and infection of target cells. These results demonstrate that PSGL-1 can serve as an IFN-regulated host factor that restricts CoV infectivity. This work was recently published (Viruses 13: 46, 2020). _____We are now focusing on defining the mechanism by which MARCH E3 ubiquitin ligases antagonize the SARS-CoV-2 S protein, evaluating the antiviral activity of GBP ATPases against the SARS-CoV-2 S protein, and measuring the expression of host cell anti-SARS-CoV-2 S protein antagonists in relevant cell types.

在我们最近开始的SARS-CoV-2 S蛋白的结构和功能分析中，我们已经确定MARCH 8，而不是催化失活的MARCH 8突变体，靶向SARS-CoV，MERS-CoV和SARS-CoV-2的S蛋白进行降解。我们还表明，人气道上皮细胞表达MARCH 8后，用IFN治疗。关于MARCH蛋白介导的拮抗作用的工作可能揭示S蛋白运输和掺入病毒颗粒的治疗干预的新机会。这项工作最近发表（mBio 12：e00219-21，2021）。在另一项研究中，我们发现PSGL-1在SARS-CoV和SARS-CoV-2假病毒粒子上的病毒粒子掺入阻断了S蛋白介导的病毒附着和感染靶细胞。这些结果表明，PSGL-1可以作为一个干扰素调节的宿主因子，限制冠状病毒的感染性。这项工作最近发表（病毒13：46，2020）。我们目前正致力于确定MARCH E3泛素连接酶拮抗SARS-CoV-2 S蛋白的机制，评估GBP ATP酶对SARS-CoV-2 S蛋白的抗病毒活性，并测量宿主细胞抗SARS-CoV-2 S蛋白拮抗剂在相关细胞类型中的表达。