Role of Pattern Recognition Receptors in Protection Against Influenza Virus

项目摘要 流感病毒导致一种严重的呼吸道疾病，每年影响近五分之一的美国人，导致 226,000人住院，49,000人死亡。除了每年的季节性爆发外，流感病毒还可以 在人类中引起频繁的流行病和偶尔的大流行。甲型流感病毒还可以感染多种 其他物种包括家禽、水鸟、马、猪和海豹。因此，流感病毒不是一种威胁 不仅对人类，而且对家禽和野生动物，以及病毒的爆发都可能产生重大的社会经济影响 影响全球。越来越多的证据表明，对流感感染的早期先天免疫反应 在很大程度上决定着感染的结局和宿主的生存。对流感病毒的早期反应 感染是由被称为“模式识别受体”的先天免疫感受器的激活而启动的 (PRRS)“存在于宿主细胞中。它们检测病毒成分并触发I型病毒的产生 干扰素(IFNA/b)和其他细胞因子。这第一个反应对于有效地安装抗病毒药物至关重要。 对病毒的反应和适当的适应性免疫反应的发展。不足为奇的是，流感 病毒通过其多功能蛋白NS1在几个细胞步骤中阻断I型干扰素的产生，从而 抑制宿主的免疫反应。然而，对早期的先天免疫反应知之甚少。 由PRRs激活，它们的激活如何控制病毒复制，参与的呼吸系统细胞类型 NS1在流感病毒毒力中的保护作用和贡献。这些研究在调查中具有挑战性 活体，部分原因是没有高效的复制能力强的病毒表达容易追踪的报告 吉恩。因此，目前的建议旨在更好地从根本上了解(Aim1)的详细情况 PRRs与流感病毒相互作用的动态及(AIM2)病毒-宿主拮抗剂的重要性 NS1在限制宿主免疫反应和病毒致病方面的作用，使用最近产生的流感 GFP/RFP报告病毒。从这项研究中获得的信息可以被用来开发新的 预防流感病毒传播和减少疾病的治疗策略。

Project Summary Influenza virus causes a serious respiratory illness affecting nearly 1 out of 5 Americans annually, resulting in 226,000 hospitalizations and up to 49,000 deaths. Apart from yearly seasonal outbreaks, influenza virus can cause frequent epidemics and occasional pandemics in humans. Influenza A virus can also infect a variety of other species including poultry, aquatic birds, horses, pigs and seals. Hence, influenza viruses are a threat not only humans but also to domestic poultry and wildlife, and viral outbreaks can have a major socio-economic impact worldwide. Accumulating evidence indicates that early innate immune responses to influenza infection largely determine the outcome of the infection and survival of the host. This early response to influenza virus infection is initiated by the activation of innate immune sensors called the "pattern-recognition receptors (PRRs)" present in the host cell. They detect the viral components and trigger the production of type I interferon (IFNa/b) and other cytokines. This first response is critical for effectively mounting antiviral responses against the virus and development of proper adaptive immune response. Not surprisingly, influenza virus blocks the production of type I IFN at several cellular steps via its multifunctional protein NS1 and thereby dampens the host immune response. However, little is known about the early innate immune responses activated by PRRs, how their activation controls viral replication, the respiratory cell types involved in protection and contribution of NS1 in influenza virus virulence. These studies are challenging to investigate in vivo, partly because there is no efficient replication-competent virus expressing an easily traceable reporter gene. So, the current proposal is aimed to gain a stronger fundamental understanding of (Aim1) the detailed dynamics of interplay between PRRs and influenza virus, and (Aim2) the importance of viral-host antagonist NS1 in limiting host immune response and viral pathogenesis, using the recently generated influenza GFP/RFP reporter viruses. The information gained from this study can be exploited in developing new therapeutic strategies to prevent influenza virus spreading and reducing disease.