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.
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.
|Schoggins, John W; MacDuff, Donna A; Imanaka, Naoko et al. (2014) Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature 505:691-5|