Mechanisms of RNA virus-host interaction

RNA病毒与宿主相互作用的机制

• 批准号: 7076965
• 负责人: SAILEN BARIK
• 金额: $ 24.95万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7076965
• 关键词: RNA interference; actin binding protein; actins; gene expression; genetically modified animals; host organism interaction; laboratory mouse; protein protein interaction; respiratory syncytial virus; transcription factor; virus genetics; virus infection mechanism; virus protein

DESCRIPTION (provided by applicant): RNA viruses, in general, are deadly human pathogens, and highly efficient in evading antivirals and vaccines, due in part to their ability to mutate rapidly. The annual Flu epidemics and the recent emergence of SARS are important reminders. The long-term goal of this project is to understand the major areas of host-virus interaction in the gene expression and signal transduction of negative-strand RNA viruses, using primarily the human respiratory syncytial virus (RSV) as a model. RSV is a severe lung pathogen in children, causing respiratory diseases and asthma, and claiming nearly a million lives globally each year. In the US alone, RSV infection leads to about 100,000 hospitalizations, costing roughly $350 million to the US taxpayers. The immunopathology of RSV also is highly complex, making it difficult to formulate a reliable vaccine or antiviral. We reasoned that a prudent approach to the management of RSV should take into account the host-virus interactive pathways. In the last few years, we have shown that cellular actin is an essential transcription factor for RSV. Our recent studies using phenotypic knockdown of cellular proteins by a relatively novel strategy, known as "RNA interference", have revealed an essential role of 3 cytoskeletal-regulatory proteins (CRPs) in RSV maturation. These proteins are: profilin, VASP, and zyxin. Previous studies demonstrated that these proteins were relatively non-essential for the host cell. Thus, we propose that these CRPs could be potential targets for an antiviral regimen. Moreover, an understanding of their role in RSV morphogenesis would shed light on the fundamental mechanism of how the cytoskeleton may play a critical role in RNA viral maturation. Thus, the Specific Aims of the proposal involve detailed studies of: (i) the role of actin as a viral transcription factor; and (ii) the involvement of the CRPs in viral morphogenesis. The available CRP knockout mice strains will be used to complement and extend these studies to an animal model. Together, these results should lead to a better understanding of the replication of RSV in particular and of RNA viruses in general, and pave the way for a more reliable management of the viral diseases.

描述（由申请人提供）：RNA病毒一般来说是致命的人类病原体，并且能够高效地逃避抗病毒药物和疫苗，部分原因是它们能够快速突变。每年的流感流行和最近出现的非典都是重要的提醒。该项目的长期目标是主要使用人类呼吸道合胞病毒（RSV）作为模型，了解负链RNA病毒的基因表达和信号转导中宿主与病毒相互作用的主要领域。 RSV 是一种严重的儿童肺部病原体，可引起呼吸道疾病和哮喘，每年夺去全球近百万人的生命。仅在美国，RSV 感染就导致约 10 万人住院治疗，给美国纳税人带来了约 3.5 亿美元的损失。 RSV 的免疫病理学也非常复杂，因此很难配制可靠的疫苗或抗病毒药物。我们认为，谨慎的 RSV 管理方法应考虑宿主与病毒的相互作用途径。在过去的几年中，我们已经证明细胞肌动蛋白是 RSV 的重要转录因子。我们最近的研究通过一种相对新颖的策略（称为“RNA 干扰”）使用细胞蛋白的表型敲低，揭示了 3 种细胞骨架调节蛋白 (CRP) 在 RSV 成熟中的重要作用。这些蛋白质是：profilin、VASP 和 zyxin。先前的研究表明，这些蛋白质对于宿主细胞来说相对不是必需的。因此，我们建议这些 CRP 可能成为抗病毒方案的潜在靶点。此外，了解它们在 RSV 形态发生中的作用将有助于揭示细胞骨架如何在 RNA 病毒成熟中发挥关键作用的基本机制。因此，该提案的具体目标涉及以下方面的详细研究：（i）肌动蛋白作为病毒转录因子的作用； (ii) CRP 参与病毒形态发生。现有的 CRP 敲除小鼠品系将用于补充这些研究并将其扩展到动物模型。总之，这些结果应该有助于更好地了解 RSV（特别是 RSV）和一般 RNA 病毒的复制，并为更可靠地管理病毒性疾病铺平道路。