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.

所有正链 RNA 病毒都需要宿主膜进行繁殖，甚至是无包膜病毒，例如 在某些情况下，病毒只是劫持宿主细胞膜并完整地利用它们。 在其他情况下，病毒重塑整个宿主脂质组，以创建具有独特的病毒诱导膜 磷脂成分，反过来又赋予这些膜独特的生化和 生物物理特性，以实现独特的生物功能、相关肠道病毒以及可能的许多功能。 其他病毒都属于后一类，PV 引起的转变的惊人之处在于。 他们只需要感染RNA的翻译，不需要基因组复制或宿主 这种情况表明转录后和/或翻译后。 哺乳动物细胞的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只需几分钟，并且一个或几个主调节器， 可以通过 PV 进行选择，可能控制这些机制是该研究的总体前提。 在扩展期间提出的是，我们的研究将阐明调节膜的机制 我们通过了解 PV 如何劫持和利用这些机制来了解生物发生、功能和运输。 将追求以下具体目标： 目标 1 - 研究 3CD 对病毒体组装、贩运、 目标 2 – 通过 PV 结合 c-Fos 诱导磷脂生物合成和膜 生物发生；和目标 3 – 宿主脂质组的动力学、机制和功能的表征 PV感染期间的重塑。 相关性（参见说明）： 小核糖核酸病毒对美国公共卫生目标的实现构成了现有和新出现的威胁。 该申请将为开发治疗感染的抑制剂提供新的靶点和机制 由小核糖核酸病毒引起，尤其是那些尚无疫苗的病毒。