Award details

The drivers of MHC evolution during a viral pandemic

Reference	BB/V000756/1
Principal Investigator / Supervisor	Professor Jim Kaufman
Co-Investigators / Co-Supervisors
Institution	University of Edinburgh
Department	Sch of Biological Sciences
Funding type	Research
Value (£)	444,750
Status	Current
Type	Research Grant
Start date	01/04/2021
End date	31/03/2024
Duration	36 months

Abstract

Classical MHC genes are the most polymorphic region of most vertebrate genomes, and this variation affects susceptibility to infectious and autoimmune disease. It is generally accepted that selection by pathogens is maintaining this variation, based on very detailed experiments in the laboratory on the one hand, and on epidemiology in humans and anecdotal observations on wild and farm animals on the other hand. However, the molecular details of how and why selection alters MHC allele frequencies in natural populations are largely unexplored. We propose to do this by combining modern developments in both molecular immunology and ancient DNA sequencing with a unique natural experiment-rabbits and myxomatosis. We recently reported that myxomatosis caused large shifts in MHC allele frequencies in French, UK and Australian rabbit populations. As we have access to both MHC molecules and viruses from before and after the myxomatosis pandemic, we are uniquely placed to understand their evolution. We will sequence rabbit MHC genes from the Neolithic to present day and identify alleles favoured following the release of myxomatosis. By cloning these alleles, we can reconstruct how natural selection has altered MHC expression and the repertoire of viral peptides that MHC molecules present. This will allow us to examine whether the selected MHC alleles simply bind the largest number of peptides or all bind a few particular (kinds of) peptides (the generalist versus specialist hypothesis), or whether the selected MHC alleles all bind the same (kinds of) peptides or have divergent peptide-binding properties (the supertype versus divergent allele hypotheses). Finally, we will compare viruses from the 1950s and modern populations, and examine whether they have evolved to escape host immunity by altering the peptides bound by MHC. While this is known to occur in small RNA viruses, it is unclear whether escape mutations are important in pathogens with larger genomes.

Summary

Within animal populations including humans, there is considerable variation between individuals in their immune responses, and among the most important causes of this variation are the MHC molecules, which allow immune systems to detect and respond to infection. MHC molecules are extremely variable between individuals, and for any given infectious organism (pathogen), some MHC molecules are more efficient than others. However, this variation not only determines whether humans and other animals can defend themselves against infection, but also whether they develop autoimmune disorders such as arthritis and asthma. Despite decades of research, there is still much to understand about how and why these genes become so variable. Studying MHC variation in humans, biomedical model organisms such as mice, and in farm animal species such as chickens has provided much fundamental information, but many factors complicate such studies. For instance, among a number of limitations, the availability of modern medical interventions in humans is difficult to disentangle from the effects of natural selection. Because MHC variation is a consequence of animals adapting to the ever-changing array of pathogens that they encounter in nature, it is essential to study MHC evolution in natural populations. We recently found that the MHC of rabbits evolved rapidly after the pandemic of the viral disease myxomatosis that has devastated rabbit populations over the last 70 years, with the same changes occurring independently in Australia, France and the UK. We propose to use these natural experiments to understand both how the properties of MHC molecules change as an animal population evolves resistance to a new pathogen, and how the pathogen counters these defences to escape the immune response. This is a unique opportunity to understand MHC evolution as not only do we have access to the 1950s and modern forms of both the MHC molecules and the virus, but we have three independent replications of the experiment in Australia, France and the UK. First, we will sequence the MHC genes from archaeological remains, museum specimens and wild rabbits. This will reveal how MHC molecules evolved over the last 5000 years, and how they changed with the arrival of myxomatosis. Using these sequences, we will then investigate how the properties of the MHC molecules have changed. In particular we can test a new hypothesis we have proposed, that epidemics of a single pathogen select for MHC molecules that not only recognise that pathogen very well but are also highly abundant within cells. Finally, by comparing 1950s and modern viruses, we can test whether the virus has evolved to escape recognition by MHC molecules. While this latter process is known to occur in small viruses like HIV, this process is not understood for larger more complex viruses. Our study is unique in utilising cutting-edge technologies for studying the molecular functioning of immune systems and applying them to understand evolution in a natural ecological setting. By using the myxomatosis pandemic-a simple natural experiment replicated several times-we will gain fundamental insights into the reasons why animal immune systems are so variable, with potential application to human biomedicine, veterinary medicine and conservation.

Impact Summary

Pathways to Impact (for the grant but with parts focused on the Kaufman lab) The Conservation and Control of Rabbits and Hares Myxomatosis is of considerable economic and conservation importance in many regions of the world, and its impact is shaped by the evolution of resistance in the host populations. In Spain the disease was reported this year to have jumped into hares where it is causing widespread mortality. There has been concern that UK hares may succumb soon. Rabbit populations are still controlled by the disease. In the introduced range, notably Australia, this is viewed as a considerable economic and ecological benefit. However, in the native range of rabbits it is a conservation problem, especially to rabbit predators like lynx. Evolution in the rabbit and virus populations has led to large increases in rabbit population sizes since the virus was first released, so our fundamental research into viral resistance can inform these sectors. We propose in engage with stakeholders in these areas. In this regard, the main activity to which the Kaufman group will contribute is a two day workshop at the start of Year 2 in Cambridge organised by the Jiggins group, to which representatives from these groups and other interested bodies will be invited. This will focus on the lessons that can be learnt from myxomatosis that can be applied to hares. For example, the genetics of immunity has turned out to be essential for evolving resistance to this virus, and therefore maintaining genetic diversity is important. The ability to understand and improve protective vaccine responses is another such message. This workshop will allow the lessons of our research to be disseminated to these groups. Public Engagement No other wildlife disease is as familiar to the public as myxomatosis- rabbits are abundant, the symptoms conspicuous, and rabbits die above ground and do not flee from encounters with humans. This public profile was reflected in the international media attention during 2019 following the publication of our paper on myxomatosis resistance. This makes our proposed work an excellent opportunity to engage the public. We therefore propose activities that aim to use our research to increase public understanding of wildlife disease, evolutionary genetics and immunity. 1) Edinburgh Science Festival: Like Cambridge, Edinburgh hosts a Science Festival, reputed to be one of Europe's largest (www.edinburghfestivalcity.com/festivals/edinburgh-science-festival), scheduled for April each year. Although the Kaufman lab is moving to Edinburgh only at the start of 2020 and therefore we have everything to learn about how it works, we intend to participate fully as we have every year in Cambridge. 2) Media: The Kaufman group has some experience with media and other forms of outreach. In particular, our 2013 PNAS paper describing the biological mechanisms by which a contagious cancer of Tasmanian devils evades the immune response led to over 30 interviews with print, radio and TV media, with an appearance of the PDRA at that time on BBC World News, and with several camera crews in the lab. It is well possible that a relatively simple and digestible message may emerge from the collaboration of the Jiggens and the Kaufman labs, particularly by abstraction of the lessons of myxomatosis to human infectious diseases like HIV/AIDS and to human cancer. Like Cambridge, the University of Edinburgh has a communications and outreach office which we will be in contact with to consider ways forward.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Animal Health, Immunology, Structural Biology
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

Associated awards:

BB/V000667/1 The drivers of MHC evolution during a viral pandemic

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