Mechanistic and Pathway Analysis of Animal Influenza Virus cross-species transmission by constructing genotype and phenotype networks

Influenza A virus (IAV) is a ubiquitous virus in wild birds that poses a constant infection threat to domesticated animals and humans. In the majority of cases, the avian strains of IAV do not replicate well in mammals and cause little to no disease. More rarely, they can infect and cause severe disease, but cannot efficiently spread from the initially infected animal or person. However, the virus can evolve to become fully transmissible in the new mammalian host and this poses the risk of provoking a global pandemic if the virus jumps into humans - as happened in 1918 and again in 2009. Surveillance can identify these dangerous strains of IAV at the earlier stages when they can only cause limited infections, but it is currently impossible to predict the risk of the virus evolving further to reach pandemic status, or to predict how virulent it might be if it did. This project aims to fill this knowledge gap by studying three strains of IAV that are currently causing concern: H5N1 highly pathogenic avian influenza, H3N8 low pathogenicity avian influenza and H1N1 G4 swine influenza. These viruses have already evolved to be capable of infecting humans and/or transmitting between other mammal species, so we will use a combination of molecular virology and computational biology approaches to understand how they have evolved to reach this threat level. We will determine the viral genome sequence features that set how the three key parameters of virus behaviour - ability to replicate, transmit and cause disease - are interlinked by creating mutant versions of them and studying these phenotypes. Importantly, because these strains of IAV have already evolved transmissibility, we can do these experiments safely by using "loss-of-function" approaches in which we aim to make the viruses less dangerous. State of the art computational approaches will quantify the results of the laboratory experiments and place them into the broader context of the global efforts to understand influenza, with the aim of producing computer models able to threat assess the likely behaviour of future strains of IAV as they appear.