A single mutation in an influenza virus can turn a bird flu that barely infects humans into a pandemic threat—and researchers have no way to predict which mutation that will be. This project tackles that blind spot. Current surveillance can spot dangerous influenza strains when they first appear in mammals, but it cannot tell whether those strains will evolve to spread efficiently between people or how severe the resulting disease might be. The researchers will study three concerning viruses—H5N1, H3N8, and H1N1 G4 swine flu—that have already jumped into mammals. By creating mutant versions that are less dangerous and measuring how changes in their genetic code alter their ability to replicate, transmit, and cause disease, they aim to build computer models that can assess the pandemic risk of future strains as they emerge. If successful, the work could transform pandemic preparedness. Instead of reacting after a virus has already spread, public health agencies could prioritise surveillance and vaccine development for the strains most likely to cause the next outbreak. The research is fundamental science—it seeks to understand the rules that govern how influenza viruses evolve—but those rules have direct practical consequences for global health security.
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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.
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