Mechanisms of RNA virus-host interaction

描述（由申请人提供）：RNA病毒通常是致命的人类病原体，并且在逃避抗病毒药物和疫苗方面非常有效，部分原因是它们能够快速突变。一年一度的流感疫情和最近出现的非典都是重要的提醒。本项目的长期目标是了解负链RNA病毒基因表达和信号转导中宿主-病毒相互作用的主要领域，主要使用人呼吸道合胞病毒（RSV）作为模型。RSV是一种严重的儿童肺部病原体，引起呼吸道疾病和哮喘，每年在全球夺去近100万人的生命。仅在美国，RSV感染就导致约10万人住院治疗，给美国纳税人造成约3.5亿美元的损失。RSV的免疫病理学也是高度复杂的，使得难以配制可靠的疫苗或抗病毒药物。我们推断，RSV管理的谨慎方法应考虑宿主-病毒相互作用途径。在过去的几年中，我们已经表明，细胞肌动蛋白是一个重要的转录因子的RSV。我们最近的研究使用表型敲低细胞蛋白质的一个相对新颖的策略，称为“RNA干扰”，揭示了一个重要的作用，3细胞调节蛋白（CRP）在RSV成熟。这些蛋白质是：profilin，VASP和zyxin。以前的研究表明，这些蛋白质是相对非必需的宿主细胞。因此，我们认为这些CRP可能是抗病毒治疗方案的潜在靶点。此外，了解它们在RSV形态发生中的作用将有助于阐明细胞骨架如何在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;以及（ii）CRP参与病毒形态发生。可用的CRP敲除小鼠品系将用于补充并将这些研究扩展至动物模型。总之，这些结果将导致更好地理解RSV的复制，特别是RNA病毒的复制，并为更可靠的病毒性疾病管理铺平道路。

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.