Projects
Mechanistic and Pathway Analysis of Animal Influenza Virus cross-species transmission by constructing genotype and phenotype networks
Topic: African Swine Fever
Summary
The risk posed by current zoonotic influenza A viruses (IAV) is high. Recent isolates of H5N1 HPAIV have, for the first time, transmitted between laboratory and farmed mustelids without prior laboratory adaptation. A novel H3N8 avian IAV reassortant has caused human cases in multiple provinces in China. The G4 lineage of H1N1 SIV transmits efficiently between ferrets in the laboratory and shows evidence of infecting humans. The IAV genetics involved in crossing the initial host range barrier are partially understood, as well as testable in in vitro systems. Aspects of pathogenicity can also be inferred from virus sequence, as well as tested in animal systems. However, while transmission can be phenotypically assessed in animal models, our ability to predict from sequence is limited; partly because of gaps in understanding the molecular determinants of the process but also because we do not fully understand the balance between viral replicative fitness (F), transmissibility (T) and pathogenicity (P) in the different host systems and how these interact with viral genetic mutation and evolution. To address these gaps, this proposal focusses on three major IAV lineages showing zoonotic potential that have already naturally evolved mammalian transmissibility, using these to perform loss of function experiments probing this "F-T-P" triad. To provide wider context and broaden the impact of this research, we will use these and other data to develop a novel framework for assessing epidemic potential of new influenza variants. This will involve state-of-the-art high-throughput sequencing, phylodynamics, and machine learning methods, parameterized and tested through molecular virology conducted in leading institutions in the UK and China. This framework will enable systematic identification of the genetic variation pathway through which novel IAV variants acquire phenotypic adaptation to and transmissibility between mammals.
Objectives & Deliverables
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.
Principle Investigator(s)
Planned Completion date: 01/02/2028
Effort: £508,970
Project Status
Active
Principal Investigator(s)
ISPF
Researcher Organisations
University of Edinburgh
United Kingdom