Mechanisms of RNA virus-host interaction

描述（由申请人提供）：一般来说，RNA病毒是致命的人类病原体，由于其快速突变的能力，RNA病毒在躲避抗病毒药物和疫苗方面效率很高。每年的流感流行和最近出现的SARS都是重要的提醒。该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，主要使用人类呼吸道合胞病毒（RSV）作为模型。呼吸道合胞病毒是儿童中一种严重的肺部病原体，可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，呼吸道合胞病毒感染就导致大约10万人住院，给美国纳税人造成大约3.5亿美元的损失。RSV的免疫病理也非常复杂，因此很难研制出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-病毒相互作用途径。在过去的几年里，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，即“RNA干扰”，利用细胞蛋白的表型敲低，揭示了3种细胞骨架调节蛋白（CRPs）在RSV成熟过程中的重要作用。这些蛋白质是：profilin， VASP和zyxin。先前的研究表明，这些蛋白质对宿主细胞来说是相对非必需的。因此，我们提出这些crp可能是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在病毒形态发生中的作用。可用的CRP敲除小鼠菌株将用于补充和扩展这些研究到动物模型。总之，这些结果将有助于更好地理解RSV的复制，特别是RNA病毒的复制，并为更可靠地管理病毒性疾病铺平道路。

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.