Role of Pattern Recognition Receptors in Protection Against Influenza Virus

描述(申请人提供)：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，多达49,000人死亡。除了每年的季节性暴发外，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其他各种物种，包括家禽、水禽、马、猪和海豹。因此，流感病毒不仅对人类构成威胁，而且对家禽和野生动物也构成威胁，病毒暴发可在世界范围内产生重大的社会经济影响。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了感染的结局和宿主的生存。这种对流感病毒感染的早期反应是由宿主细胞中存在的被称为“模式识别受体(PRRs)”的先天免疫传感器启动的。它们检测病毒成分，并触发I型干扰素(干扰素-a/β)和其他细胞因子的产生。这第一个反应对于有效地建立针对病毒的抗病毒反应和发展适当的适应性免疫反应至关重要。毫不奇怪，流感病毒通过其多功能蛋白NS1在几个细胞步骤阻止I型干扰素的产生，从而抑制宿主的免疫反应。然而，关于PRRs激活的早期先天免疫反应、它们的激活如何控制病毒复制、参与保护的呼吸系统细胞类型以及NS1在流感病毒毒力中的作用，人们知之甚少。这些研究在体内研究具有挑战性，部分原因是没有有效的复制能力病毒表达易于追踪的报告基因。因此，目前的建议旨在通过使用最近产生的流感GFP/RFP报告病毒，对(Aim1)PRRs和流感病毒之间相互作用的详细动力学以及(AIM2)病毒-宿主拮抗剂NS1在限制宿主免疫反应和病毒致病中的重要性有更深入的基础了解。从这项研究中获得的信息可以被用来开发新的治疗策略，以防止流感病毒的传播和减少疾病。针对流感病毒感染的早期先天免疫反应对及时控制感染起着至关重要的作用，而宿主早期免疫反应的好坏决定着宿主的命运。这项建议使用携带荧光记者的新产生的流感病毒，旨在了解宿主先天免疫传感器如何帮助控制病毒感染，以及病毒因子(S)如何限制宿主免疫反应。这些知识可能有助于设计针对流感病毒的新疗法。

DESCRIPTION (provided by applicant): 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 (IFN-a/¿) 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. Early innate immune response against the influenza virus infection plays a critical role in the timely control of infection, and the quality of the early host response determines the fate of the host. This proposal, using the newly generated influenza virus carrying fluorescent reporters, aims to understand how the host innate immune sensors help control virus infection and how the viral factor(s) limit host immune response. This knowledge can be useful in devising novel therapeutics against influenza viruses.