Picornavirus Genome Replication

小核糖核酸病毒基因组复制

• 批准号: 10447359
• 负责人: CRAIG E. CAMERON
• 金额: $ 53.4万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10447359
• 关键词: Achievement; Anabolism; Biochemical; Biological Process; Categories; Cytoplasm; Development; Enterovirus; FOS gene; Family Picornaviridae; Genetic Transcription; Genome; Goals; Human poliovirus; Infection; Instruction; Mammalian Cell; Membrane; Phospholipids; Picornaviridae Infections; Public Health; RNA; RNA Viruses; Research; Translations; Vaccines; Virion; Virus; biophysical properties; falls; inhibitor; lipidome; membrane biogenesis; novel; posttranscriptional; trafficking

All positive-strand RNA viruses require host membranes for multiplication, even non-enveloped viruses like poliovirus (PV). In some cases, viruses simply hijack host membranes and use them intact. However, in other cases, viruses remodel the entire host lipidome to create virus-induced membranes with unique phospholipid composition, which, in turn, confers upon these membranes unique biochemical and biophysical properties to enable unique biological function. PV, related enteroviruses, and likely many other viruses, fall into this latter category. What is so astonishing about the PV-induced transformations is that they only require translation of the infecting RNA, without the need for genome replication or host transcription. What this circumstance suggests is that post-transcriptional and/or post-translational mechanisms exist in the mammalian cell cytoplasm capable of completely reprogramming phospholipid biosynthesis and membrane biogenesis in a matter of minutes and that one or a few master regulators, which can be coopted by PV, likely control these mechanisms. The overarching premise of the research proposed during the extension is that our studies will illuminate mechanisms regulating membrane biogenesis, function, and trafficking by understanding how PV hijacks and coopts these mechanisms. We will pursue the following specific aims: Aim 1 - Study contributions of 3CD to virion assembly, trafficking, and egress; Aim 2 – Coopting of c-Fos by PV to induce phospholipid biosynthesis and membrane biogenesis; and Aim 3 – Characterization of the dynamics, mechanisms, and functions of host-lipidome remodeling during PV infection. RELEVANCE (See instructions): Picornaviruses represent an existing and emerging threat to U.S. public health. Achievement of the goals of the application will provide novel targets and mechanisms for development of inhibitors to treat infections by picornaviruses, especially those for which vaccines are not available.

所有的正链RNA病毒都需要宿主细胞膜才能增殖，即使是无包膜病毒， 脊髓灰质炎病毒（PV）。在某些情况下，病毒只是劫持宿主的细胞膜并完整地使用它们。但在 在其他情况下，病毒重塑整个宿主脂质组，以产生具有独特的 磷脂组合物，这反过来又赋予这些膜独特的生物化学和生物活性。 生物物理特性，以实现独特的生物功能。PV、相关肠道病毒，可能还有很多 其他病毒属于后一类。光伏引起的转变最令人惊讶的是 它们只需要感染RNA的翻译，而不需要基因组复制或宿主。 转录。这种情况表明，转录后和/或翻译后 在哺乳动物细胞质中存在能够完全重编程磷脂的机制 生物合成和膜生物发生在几分钟内，一个或几个主调节器， 可能控制这些机制。研究的首要前提是 在扩展过程中提出的是，我们的研究将阐明调节膜的机制， 生物发生，功能和运输，通过了解PV如何劫持和coopt这些机制。我们 将追求以下具体目标：目标1 -研究3CD对病毒体组装，贩运， 目的2 -PV对c-Fos的捕获诱导磷脂生物合成和膜 目的3 -宿主脂质体的动力学、机制和功能的表征 肺静脉感染期间的重塑。 相关性（参见说明）： 小核糖核酸病毒是对美国公共卫生的现有和新兴威胁。各项目标实现情况 该应用将为开发治疗感染的抑制剂提供新的靶点和机制 小核糖核酸病毒，特别是那些没有疫苗的病毒。