Mechanisms of RNA virus-host interaction

描述(申请人提供)：RNA病毒通常是致命的人类病原体，在躲避抗病毒药物和疫苗方面非常有效，部分原因是它们有快速变异的能力。每年的流感疫情和最近出现的SARS都是重要的提醒。该项目的长期目标是主要以人类呼吸道合胞病毒(RSV)为模型，了解负链RNA病毒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，会导致呼吸道疾病和哮喘，每年在全球夺走近100万人的生命。仅在美国，RSV感染就导致约10万人住院，给美国纳税人造成了约3.5亿美元的损失。RSV的免疫病理学也非常复杂，很难研制出可靠的疫苗或抗病毒药物。我们认为，对呼吸道合胞病毒的谨慎管理应考虑到宿主与病毒的相互作用途径。在过去的几年里，我们已经证明细胞肌动蛋白是RSV必不可少的转录因子。我们最近的研究利用一种相对新颖的策略--“RNA干扰”--对细胞蛋白质进行表型敲除，揭示了3种细胞骨架调节蛋白(CRP)在RSV成熟过程中的重要作用。这些蛋白质是：Profilin、Vasp和Zysin。以前的研究表明，这些蛋白质对宿主细胞相对来说不是必需的。因此，我们认为这些CRP可能成为抗病毒治疗的潜在靶点。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，该提案的具体目标包括详细研究：(I)肌动蛋白作为病毒转录因子的作用；以及(Ii)CRPS在病毒形态发生中的参与。可用的CRP基因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的复制，特别是RNA病毒的复制，并为更可靠地管理病毒疾病铺平道路。

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.