RSV and SARS Coronavirus Pathogenesis

RSV 和 SARS 冠状病毒发病机制

• 批准号: 7592400
• 负责人: Barney Scott Graham
• 金额: $ 77.5万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 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/7592400
• 关键词: Cells; Cholesterol; Coronavirus; Cyclodextrins; Disruption; Giant Cells; Glycoproteins; HIV-1; Hepatitis C; In Vitro; Infection; Influenza; Isoprenylation Inhibition; Lipids; Mediating; Membrane; Membrane Fusion; Membrane Microdomains; Modeling; Morphogenesis; Mus; Numbers; Para-Influenza Virus Type 3; Pathogenesis; Pathogenicity; Peptides; Production; Protocols documentation; Respiratory syncytial virus RSV F glycoprotein; Role; Rotavirus; SARS coronavirus; Severe Acute Respiratory Syndrome; Structural Protein; Time; Viral; Viral Proteins; Virus; Work; in vivo; particle

Respiratory syncytial virus F glycoprotein was shown to interact with RhoA and RhoA-derived peptides were shown to inhibit RSV infection in vitro and in a murine model. In addition, RhoA-derived peptides inhibited other viruses (Parainfluenza virus Type 3 and HIV-1) with similar glycoprotein-mediated membrane fusion mechanisms. Further studies showed that RhoA was activated during RSV infection and that inhibiting RhoA activation could alter the syncytium-forming capacity of the virus, and virus morphogenesis, resulting in less filamentous virus. Inhibiting RhoA targeting to membrane through isoprenylation inhibition, could diminish RSV replication and reduce pathogenicity in the murine model. In part, this works through shifting the assembly of RSV from cholesterol-rich lipid microdomains to other regions of the membrane. Lipid microdomains have been shown to be involved in the assembly and production of a number of viruses, including HIV-1, influenza, hepatitis C, and rotavirus. This work investigates the role of lipid microdomains in formation of RSV and severe acute respiratory syndrome coronavirus (SARS-CoV) by examining the colocalization of viral proteins with lipid microdomain components and by evaluating the effects of lipid raft disruption on viral infectivity. The SARS-Co) encodes 4 main structural proteins, M, N, E, and S, three of which mediate SARS-CoV pseudo particles. These particles preferentially bud from lipid rafts, and disruption of lipid rafts with cyclodextrin diminishes particle formation.

显示呼吸道合胞病毒F糖蛋白与RhoA相互作用，而RhoA衍生的肽显示可在体外和鼠模型中抑制RSV感染。此外，RhoA衍生的肽抑制了具有相似糖蛋白介导的膜融合机制的其他病毒（parainfluenza病毒3型和HIV-1）。进一步的研究表明，在RSV感染过程中激活了RhoA，并且抑制RhoA激活可能会改变病毒的合成能力和病毒形态发生，从而导致丝状病毒较少。通过异源义抑制抑制RhoA靶向膜，可以减少RSV复制并降低鼠模型中的致病性。在某种程度上，这是通过将RSV组装从富含胆固醇的脂质微域转移到膜的其他区域的作用。脂质微域已被证明参与了许多病毒的组装和产生，包括HIV-1，流感，乙型肝炎和轮状病毒。这项工作通过检查病毒蛋白与脂质微域成分的共定位以及评估脂质抗体破坏病毒感染性的影响，研究了脂质微域在RSV和严重急性呼吸综合征冠状病毒（SARS-COV）中的作用。 SARS-CO）编码4个主要结构蛋白，M，N，E和S，其中三个介导SARS-COV伪颗粒。这些颗粒优先从脂质筏中芽，并用环糊精的脂质筏破坏会减少颗粒的形成。