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Antiviral restriction factors: Understanding determinants of host range and barriers to species-jumping in livestock viral disease

Reference	BB/X009084/1
Principal Investigator / Supervisor	Dr Tobias Tuthill
Co-Investigators / Co-Supervisors	Dr James Kelly, Dr Andrew Shaw
Institution	The Pirbright Institute
Department	Picornavirus Molecular Biology
Funding type	Research
Value (£)	434,794
Status	Current
Type	Research Grant
Start date	01/05/2023
End date	30/04/2026
Duration	36 months

Abstract

Studies of the biological factors governing virus host range have traditionally focused on receptor tropism. However, for numerous viruses, receptor usage does not appear to contribute to host range. For example, the picornavirus FMDV circulates in livestock species such as cows and pigs, but does not cause disease in humans or horses, despite the human and equine receptors allowing efficient cell entry in vitro, indicating the presence of non-receptor-based barriers to infection in these species. We observed that, in human cells, efficient replication was prevented by the presence of an intact interferon (IFN) response. Further, by screening libraries of ISGs, we identified primate-specific restriction factors which prevent infection in vitro but which do not exist in FMD-susceptible species. We have further characterised one of these genes and shown that it does not restrict infections of a related human picornavirus, indicating that human viruses may be adapted to avoid restriction by these ISGs. In this proposal, we intend to characterise the roles which these ISGs play in preventing FMDV infections in humans and other mammals. To do this, we will first overexpress the orthologues from a panel of different species to observe the pattern of restriction. Conversely, we will knock out these genes using siRNA and CRISPR-Cas9 approaches. Next, we will investigate if the innate immune system can protect humans from other livestock viruses, by testing the ability of the already identified ISGs to block other livestock viruses, as well as perform new ISG screens to identify further inhibitory ISGs. Finally, we will assess if and how viruses can overcome a hosts' innate immune response. To do this, we will passage viruses in the presence of restriction factors and isolate viruses which show enhanced replication. We will use next generation sequencing to study the evolution of adaptive substitutions and correlate sequence changes with virus phenotype.

Summary

The importance of host species jumping by viruses has been recently highlighted by the zoonotic spread of a coronavirus likely originating in bats, resulting in the human pandemic of COVID-19. However, viruses jumping from animals to humans is a relatively uncommon event. Most viruses are effectively marooned in their normal host species and are unable to infect other species. This is because viruses have usually become finely tuned to infect just one or a limited number of specific species. Species outside the viruses normal host range present a different host environment containing unfamiliar obstacles or barriers that can prevent virus infections. At present we have a poor understanding of most of these barriers that prevent host species jumping including those that protect humans from infections with most animal viruses. In this project we aim to identify the barriers that prevent animal viruses from jumping species, including infecting humans. A better understanding of what these barriers are could enhance our ability to predict what viruses are likely to jump from animals to humans. Improving this prediction capability could help reduce or prevent the devastating impacts of viral zoonoses. We will focus on viruses of livestock animals, because despite the high profile of zoonoses originating from wildlife, in fact 99% of zoonotic infections are caused by contact with livestock and only the remaining 1% is due to contact with wildlife trade. One established barrier is the inability of a virus to enter the cell of a species outside its natural host range. Viruses enter cells using molecules on the cell surface known as receptors and viruses can be highly specialised to use a specific receptor. Variation in receptor molecules between different species, can prevent a virus from being able to enter cells of a different species. However, cell entry is not always a barrier to infection. For example, foot-and-mouth disease virus (FMDV) causes disease in pigs andcows, but is unable to infect humans, yet it enters human cells just as effectively as bovine cells. Similar observations have been made for bovine respiratory syncytial virus (bRSV) and swine vesicular disease virus (SVDV). This means there must be other barriers that protect humans from infections with these livestock viruses. We suspect these other barriers are part of the human innate immune system, specifically interferon stimulated genes (ISGs). ISGs are activated during viral infections, there are hundreds of different ISGs, each with a specialised antiviral function, each one acting like a different "tool" on a "Swiss army antiviral knife". While the bulk of the tools are the same between different mammalian species, each species has a few tools that are unique to it. For example, humans have certain "Swiss army knife tools" that are absent in livestock animals. These unique genes may be specialised to protect humans from infections against specific viruses. We screened a library containing over 500 different human ISGs for anti-FMDV activity and have identified genes or 'restriction factors' that are not present in cows or pigs. These genes likely protect humans and some other mammals from FMDV infections. We would like to determine in greater detail how these genes in the mammalian "Swiss army antiviral knife" protects against species jumping including into humans, by FMDV and other livestock viruses.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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