来自Burnham医学研究院、Mount Sinai医学院、Salk生物研究学院、以及诺华研究基金会的基因组学研究院的科学家们发现了甲型流感病毒株感染人类细胞必须利用的295种细胞因子，包括当前流行的猪源H1N1流感。同时这个团队还筛选出几种作用于部分上述细胞因子，并抑制病毒复制的小分子复合物，为治疗流感的指明了新的方向。这些研究发表于12月21日的《自然》杂志的网络版上。

甲型流感病毒只含有足够生产11种蛋白质的遗传信息（核糖核酸），因而必须借助宿主细胞体系来完成自身的细胞周期。Burnham学院的Sumit Chanda博士、Mount Sinai学院的Megan Shaw博士、Salk学院的John Young博士、GNF的Yingyao Zhou博士和其他一些科学家使用RNAi筛选技术选择性关闭超过19，000个人类基因，以确定那些有利于病毒入侵、脱壳、核酸植入、病毒复制和其他病毒必需功能的人类因子。

“由于病毒变异如此迅速，事实上对于一种针对性疗法而言，它已成为不停移动的靶标，因此流行病毒株很难应付，包括猪H1N1流感病毒”， Chanda博士说，“结果目前的感染性病毒普遍对两种抗病毒药物产生抗体。然而，如果以更加稳定的人类宿主的细胞因子作为靶标，则很有希望开发出能狗预防或治疗各种甲型流感的新疗法，同时其疗效也可以得到最大限度的维持。”

“这项研究给我们提供了关于流感病毒用于完成复制的细胞途径和因子的重要信息”，Shaw博士补充说，“每一个上述细胞因袭都代表了这些病毒的一个‘致命要害’，这极大地增加了新的抗流感病毒药物的潜在靶标”。

该研究小组利用全基因组siRNA文库对感染了经改造的流感病毒的人A549细胞（肺上皮细胞）进行了筛选。通过两次独立的筛选工作，他们确认了295个细胞基因，选择性抑制其中任何一个的表达都可以减少病毒感染，这有力地描绘出流感病毒感染细胞的整个过程的线路图。更重要的是，他们发现，通过抑制已知的药物靶标，如激酶、vATPases和微管蛋白，均可抑制流感的发展，这表明小分子化合物很有可能被开发成宿主因子导向的抗病毒药物。蛋白质相互作用的数据分析证实，181中宿主细胞因子介导了病毒和细胞蛋白之间的4266种作用。

Burnham学院的Renate Koenig博士和Mount Sinai学院Peter Palese博士、Silke Stertz博士以及Adolfo Garcia-Sastre博士也参与了这项研究。

“试图找出流感病毒复制所需的所有宿主蛋白是一个巨大的挑战，但我们已经非常接近于‘知道’所有相关的基因。”Palese博士说。

Young博士补充说：“这些发现与其他RNAi筛选的结果一起，为我们展现了一幅更普遍地为病毒所利用的宿主细胞因子作用过程的蓝图，并指出了未来的广谱抗病毒药物的开发方向。”

关键词：抗病毒，生物技术，基因疗法，遗传学，基因组学，H1N1病毒，传染性疾病，诺华公司，制药企业，医药公司，猪流感，猪流感，技术，治疗，病毒，抑制病毒，病毒治疗，病毒学，伯纳姆研究所。

How flu succeeds

Investigators at Burnham Institute for Medical Research (Burnham), Mount Sinai School of Medicine (Mount Sinai), the Salk Institute for Biological Studies (Salk) and the Genomics Institute of the Novartis Research Foundation (GNF) have identified 295 human cell factors that influenza A strains must harness to infect a cell, including the currently circulating swine-origin H1N1. The team also identified small molecule compounds that act on several of these factors and inhibit viral replication, pointing to new ways to treat flu. These findings were published online on December 21 in the journal Nature.

Influenza A virus contains only enough genetic information (RNA) to produce 11 proteins and must co-opt host cellular machinery to complete its life cycle. Sumit Chanda, Ph.D., of Burnham, Megan Shaw, Ph.D., of Mount Sinai, John Young, Ph.D., of Salk, Yingyao Zhou, Ph.D., of GNF and others used RNAi screening technology to selectively turn off more than 19,000 human genes to determine which human factors facilitate viral entry, uncoating, nuclear import, viral replication and other necessary functions of the virus.

"Because influenza mutates so readily, it has become a moving target for theraputic intervention, making it difficult to treat circulating strains, including the H1N1 swine flu," said Dr. Chanda. "As a result, there is now widespread resistance to two classes of antiviral drugs. However, by targeting more stable human host factors, we may be able to develop therapies that prevent or treat a variety of influenza A strains and are more likely to maintain their effectiveness."

"This study has provided us with crucial knowledge of the cellular pathways and factors the influenza virus exploits to replicate" added Dr. Shaw. "Each of these represents an \'Achilles heel\' of the virus and vastly increases the number of potential targets for new influenza antiviral drugs."

The team screened human A549 (lung epithelial) cells infected with a modified influenza virus against the genome-wide siRNA library. Conducting two independent screens, they confirmed that selectively impairing each of 295 cellular genes reduced viral infection, effectively illuminating the path followed by influenza viruses during the infection of a cell. Importantly, they found that inhibiting proteins in known drug target classes, such as kinases, vATPases, and tubulin, impairs influenza growth, suggesting that small molecular weight compounds may be developed as host factor-directed antivirals. Protein interactions dataset analysis confirmed 181 host cellular factors that mediate 4,266 interactions between viral or cellular proteins.

Renate Koenig, Ph.D., of Burnham and Peter Palese, Ph.D., Silke Stertz, Ph.D., and Adolfo Garcia-Sastre, Ph.D., of Mount Sinai also collaborated on this research.

"Trying to identify all the host proteins that are required for the replication of influenza viruses is a wonderful challenge and we have come closer to \'knowing\' all the genes involved," said Dr. Palese.

Dr. Young added, "These findings, combined with those from other RNAi screens, provide a blueprint of the cellular processes that are exploited more generally by viruses, pointing towards development of future broad-spectrum antiviral approaches."

Keywords: Antiviral, Biotechnology, Gene Therapy, Genetics, Genomics, H1N1 Virus, Infectious Disease, Novartis AG, Pharmaceutical Business, Pharmaceutical Company, Swine Flu, Swine Influenza, Technology, Treatment, Viral, Viral Inhibition, Viral Therapy, Virology, Burnham Institute.

This article was prepared by NewsRx editors from staff and other reports. Copyright 2010, NewsRx.com.

Source：NewsRx