Innate Immunity and Host Species Barriers

Innate Immunity and Host Species Barrier
Prof Massimo Palmarini and Dr Sam Wilson, Lead Investigators, with Dr Robert Gifford as a co-investigator and in collaboration with Prof James Neil, MRC-University of Glasgow Centre for Virus Research (CVR), University of GlasgowViral diseases are often in the news because of their ability to suddenly cause an 'outbreak' in human populations. Often this is due to the ability of a virus from animals to 'jump' into humans and start causing disease. Currently, we don't fully understand how viruses 'jump' from one species to another, which hinders our ability to predict which viruses could threaten people in the future.
Humans and the animals we share our environment with have all been plagued by viral diseases (some of which are life-threatening) for millions of years. To resist infection, animals have evolved an arsenal of different antiviral defences and every animal has evolved a unique set of these defences. Importantly, these defences can sometimes stop a virus from 'jumping' into a new species.
By mapping the antiviral defences in humans and selected domestic and wild animals (like bats and pigs) we will catalogue the diversity of these defences in humans and 'animal reservoirs' of viral diseases. We will use this information to measure the ability of each individual defence to inhibit viruses that threaten human populations. We hope to identify the specific genes that leave us vulnerable to or protect us from the viral diseases circulating in animal populations.

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.