Role of nucleocytoplasmic trafficking of Matrix protein in RSV infection

呼吸道合胞病毒（RSV）是全世界婴幼儿病毒性肺炎的主要病因。到3岁时，几乎每个儿童都至少感染过一次RSV。RSV也是老年人肺炎的重要原因，估计每年冬天造成的死亡人数超过流感。在澳大利亚，估计每年有10万名婴儿感染RSV。在维多利亚，RSV是所有报告的呼吸道疾病病例的最常见原因，估计每年的费用为1 -4百万美元。尽管有超过40年的研究，但没有预防RSV感染的疫苗，并且唯一被许可用于治疗RSV感染的药物（利巴韦林）昂贵，难以管理，有毒，并且疗效可疑。我们建议检查RSV蛋白之一，基质蛋白（M）。M对于病毒繁殖非常重要，并且负责所产生的细胞损伤。我们已经观察到M进入细胞核（所有细胞DNA和RNA合成的位置），在感染早期它似乎抑制宿主细胞RNA合成;后来，它在细胞质中产生病毒所需的步骤中离开细胞核。调节M进出细胞核的信号以及对宿主细胞的影响导致发病机制，是该建议的重点。这项研究的结果将在许多方面有益。最重要的是，我们将获得有关RSV疾病引起的细胞损伤的过程的知识，这可能导致干预策略的新靶点的确定。

Respiratory syncytial virus (RSV) is the major cause of viral pneumonia in infants and young children throughout the world. By the age of 3, virtually every child has been infected by RSV at least once. RSV is also an important cause of pneumonia in the elderly and is estimated to cause more deaths each winter than influenza. In Australia, an estimated 100,000 infants are infected by RSV every year. In Victoria, RSV is the most common cause of all reported cases of respiratory tract disease, with an estimated annual cost of $1-4 million. Despite more than 40 years of research there is no vaccine to prevent RSV infection, and the only drug (ribavirin) licenced for treatment of RSV infection is expensive, difficult to administer, toxic, and of doubtful efficacy. We propose to examine one of the RSV proteins, the matrix protein (M). M is very important for virus propagation and is responsible for resultant cell injury. We have observed that M enters the cell nucleus (the location for all cellular DNA and RNA synthesis) where it appears to inhibit host cell RNA synthesis early in infection; later, it exits the nucleus in a step required for virus production in the cytoplasm. The signals that regulate transport of M into and out of the nucleus and the effect on the host cell leading to pathogenesis, are the focus of this proposal. The results of this study will be beneficial in many ways. Most importantly, we will gain knowledge about the processes underlying cell injury caused in RSV disease, which may lead to the identification of novel targets for intervention strategies.