Structure-function relationships of the influenza virus RNA polymerase: influence on virulence, host restriction and innate immune responses

Seasonal influenza viruses cause 3 to 5 million cases of severe infections in humans each year, leading to between 250,000 to 500,000 deaths worldwide. Influenza A viruses can also cause pandemics, through the emergence of new viral strains from wild birds and pigs, with potentially catastrophic consequences for society. Currently the H5N1 and H7N9 'bird flu' subtypes are considered the biggest threats as these are prevalent in birds and can infect humans directly, leading to severe disease and death. The concern is that these viruses, or other 'bird flu' subtypes, through adaptation or by mixing with human or swine influenza viruses, could gain the ability to easily transmit between humans and lead to a new pandemic. Current antiviral approaches are limited to vaccines that require annual updating and are unlikely to be useful against an emerging novel pandemic virus, and a few antiviral drugs against which viral resistance can develop. The focus of our research programme is the RNA polymerase of influenza viruses, a key multi-subunit enzyme complex containing multiple functional domains, considered to be a prime viral target for the development of novel antiviral drugs. The viral RNA polymerase is responsible for copying the genetic information of influenza virus that is stored in eight segments of RNA. It is directly responsible for transcribing the RNA segments into instructions to the host cell to produce viral proteins (messenger mRNA, mRNA) as well as replicating the RNA segments through complementary RNA intermediates. The viral proteins together with the replicated RNA segments assemble into new virus particles to be released from the host cell. RNA polymerases of avian influenza viruses function poorly in mammalian cells unless they undergo adaptive changes. Therefore the RNA polymerase can determine which hosts the virus infects (e.g. humans, birds or swine) and can also determine the severity and the outcome of the disease caused. However, we do not understand the molecular basis of these activities. Our research programme aims to uncover how the RNA polymerase works and takes advantage of host co-factors in the infected cell. By understanding these processes we will uncover new ways of inhibiting the polymerase, and thus preventing the virus from multiplying, spreading and causing disease. We will also learn how genetic changes in the polymerase allow an influenza virus to jump from birds to humans and cause disease. Our bodies react to viral infection by producing substances that protect us from the virus. However, infection with 'bird flu' can cause our bodies to overreact by producing far too much of these substances, actually resulting in more severe disease. We found that the polymerases of 'bird flu' viruses do not work optimally in mammalian cells and produce aberrant short RNAs that we call mini viral RNAs (mvRNAs). These mvRNAs are very strong inducers of antiviral substances and could underlie the high virulence of H5N1 and H7N9 'bird flu' viruses in humans. By elucidating how these mvRNAs are made and what their effects are, we will be able to understand what makes 'bird flu' so deadly in humans. Working with industrial partners, this knowledge could also help with the design of improved influenza vaccines that are fine-tuned to induce a precise level of antiviral substances and to give the highest level of protection to those vaccinated.