Immunodynamics and infectious disease risk in the natural environment

Individuals vary in their response to infectious disease, be they humans, livestock or wild animals. To protect human and veterinary health, and to conserve wildlife, we need to understand what makes some individuals more vulnerable to disease than others. Studies of laboratory mice have provided great insight into how the immune system works at a mechanistic level, but the bigger question of why some individuals are more vulnerable to infection cannot be resolved by this route. In the natural environment, wild animals are subject to infection by multiple pathogens and must cope with these infections while also coping with environmental stress and the pressures of finding food, finding a mate and reproducing. Similar things can still be said of humans in the poorer parts of the world. These conflicting pressures can lead to different strategies to cope with infection. First, immune responses may be produced to clear an infection; we refer to this as resistance. But this can come at a significant cost in damage to host tissue by the immune response itself (immunopathology). Alternatively, it may be better to reduce the damage caused by the infection - referred to as tolerance - particularly if an individual is constantly re-acquiring infection from the environment. The type of immune responses made depend in part on the type of pathogen to which an individual is exposed, but individuals in apparently similar circumstances nonetheless differ in their responses to infection, and some are certainly worse than others at either resisting or tolerating infection. Individuals within a natural population will differ in their genetics, level of nutrition, prior history of infection, and in the composition of their gut bacteria. All of these may affect the type or strength of immune responses that they make following infection.

Our aim, therefore, is to elaborate the genetic and environmental drivers of immunological variation in natural populations and the consequences of this variation for infection, disease (clinical symptoms of infection) and health. The benefits of this research will be to identify the types of individuals, and the environmental circumstances, that make individuals more or less vulnerable to infection and disease. This will help to conserve natural populations threatened with disease, to mitigate against zoonotic infections (infections passed from wildlife populations to humans), and to increase understanding of human immunity.

Laboratory rodents cannot give us the answers we require, and we cannot study human populations for a combination of practical and ethical reasons. Rather, to achieve our aims we will exploit a long-standing ecological study of field voles, a rodent species that is abundant in the UK, infected with multiple pathogens and for which we have now generated a genome sequence and immunological assays to measure key components of the immune response in the natural environment. It is thus a model system that will cast light on variation in responses to infectious disease generally. We will perform intensive sampling from the field, and laboratory analysis of multiple immune responses, followed by computational analysis of regulatory networks to understand how the immune responses are shaped by genetics and environment and the consequences of these responses for health and fitness.

Public engagement
This represents the most immediate impact and so activities to promote public engagement will be conducted within the timeframe of the proposal. We will work with local wildlife trusts to engage the public with the aims of this project and of NERC science. To facilitate these activities we will provide a scholarship to a student on the MSc in Biological Imaging at Nottingham University. This will allow us to produce high-quality photographic material for a public display accompanied by information delivered via augmented reality software on smart phones. These materials will focus on the field vole as an exemplar of British wildlife, its life history, and its place in the wider ecosystem. In addition to exhibits at local visitor centres and museums within Northumbria, we intend to use these in local schools for outreach activities.

Industrial collaboration.
In the longer term, i.e. beyond the timeframe of this project, our research has the potential to identify targets for novel small molecule therapeutics to modify specific aspects of the immune response. Thus our research is fundamental, but takes a novel approach to understanding immune functioning in a complex environment that could not be achieved through studies of humans or laboratory mice. Involving industrial partners from the outset of the proposal would be premature: we have to wait until we have results worth pursuing and we need to retain intellectual property (IP) within the three Universities before seeking industrial partners who can help us to exploit our results. The appropriate partner would depend on the nature of the IP and we would use the University of Liverpool Business Gateway in the first instance to help find a partner. Business Gateway has links with a wide range of SMEs and larger scale pharmaceutical companies, such as Syngenta and GSK, and through the multimillion pound investment in the Liverpool BioCampus, which draws together academic and commercial activity within the veterinary and medical arenas.