Picornavirus Genome Replication

所有的正链RNA病毒都需要宿主膜来繁殖，即使是像这样的无包膜病毒 脊灰病毒(PV)。在某些情况下，病毒只是劫持宿主膜并完好无损地使用它们。但是，在 在其他情况下，病毒重塑整个宿主脂体，以创建病毒诱导的膜，具有独特的 磷脂成分，这反过来又赋予这些膜独特的生化和 生物物理特性使其具有独特的生物功能。PV，相关的肠道病毒，以及可能许多 其他病毒属于后一类。光伏引起的变化如此令人惊讶的是 它们只需要翻译感染的RNA，而不需要基因组复制或宿主 抄写。这种情况表明，转录后和/或翻译后 哺乳动物细胞质中存在能够完全重新编程磷脂的机制 生物合成和膜生物发生在几分钟内，以及一个或几个掌握调节器， 它们可以被光伏所取代，很可能控制着这些机制。这项研究的首要前提 在扩展期间提出的是我们的研究将阐明膜的调节机制 通过了解光伏如何劫持和利用这些机制来实现生物发生、功能和贩运。我们 将追求以下具体目标：目标1--3CD对病毒粒子组装、贩运、 目的2-PV对c-Fos的共选诱导磷脂生物合成和膜 生物发生；和目标3--宿主类脂体的动力学、机制和功能的特征 PV感染过程中的重塑。 相关性(请参阅说明)： 小核糖核酸病毒对美国公共卫生构成了现有的和正在出现的威胁。目标的实现情况 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。

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.