Innate Immunity and Host Species Barriers

In vertebrates, the interferon (IFN) response is the first line of defence against viruses, stimulating the production of diverse antiviral proteins encoded by hundreds of IFN-stimulated genes (ISGs). These host defences are engaged in continuous evolutionary conflicts with viruses, which have evolved a variety of evasive counterstrategies. Most viruses are only able to efficiently infect and replicate within a limited set of species, and multiple lines of evidence indicate that the IFN response plays a key role in limiting cross-species transmission. Sometimes, however, viruses do succeed in "jumping" from one species to another - indicating that host innate defences have been overcome. Since most emerging viruses (e.g. Ebola virus, coronaviruses, Nipah virus etc.) persist in animal reservoirs, it is vital to understand the barriers that normally prevent cross-species transmission. In this programme, we will first characterise the ISGs of a variety of animal species, including reservoirs of zoonotic infections. We will then examine a range of important human pathogens (e.g. Ebola virus, hepatitis C, Dengue and others) in vitro and in silico to (i) define patterns of antiviral restriction by "homologous" and "heterologous" ISGs and (ii) identify important host and viral determinants of cross-species transmission. We will develop experimental systems that will allow us to dissect the evolutionary history of antiviral genes, and explore the pathways and constraints to the evolution of viral counterstrategies. Altogether, these data will provide a powerful and flexible system for (i) constructing predictive models (a "zoonotic index") to assess the risk of future cross-species transmission events and (ii) identifying novel antiviral genes.