Defining the Drivers of Immune Variation

The body defends itself from infection via its immune system. Animal immune systems are extraordinarily variable, but we do not understand why. In particular we do not know how heritable factors, defined by genes, and non-heritable factors such as current and previous infections, affect immune responses. The type of response that an individual produces in response to infection ultimately determines whether it resists the infection or succumbs to disease. The level and type of immune response also determines the effectiveness of vaccines and will affect the transmission of pathogens. Understanding the causes of immune variation is important if we are to explain why some individuals are more vulnerable to infection and can allow us to develop effective targeted treatment options

Studies of immune responses to infection in laboratory mice have been very important in helping us understand the types of immune response important in resisting different types of infection. However, these experiments are carried out under carefully controlled conditions which minimise all other variables. A complete understanding of the causes and consequences of immune variation can only be reached by studying immune systems in natural settings.

We will trap mice over two seasons and use two types of study: a cross-sectional study, where mice will be vaccinated or treated for their parasites, and subsequently sacrificed; and a longitudinal study, where mice will be captured, examined, a small blood sample removed and then released.

For mice in both types of study we will analyse expression of a wide range of immunological parameters, characterise infection status and obtain genetic sequences so that we can estimate their average relatedness.

Our study has three main strengths:
1) We will use a wild population of the house mouse, Mus musculus domesticus, for which we have considerable preliminary data.
2) Our characterisation of immune responses will be unrivaled in depth and breadth because we will use the immunological reagents developed for studies of laboratory mice.
3) We will follow the same individual mice for up to two years, including an experimental intervention: this will allow for the first time comprehensive data on immune responses to be correlated with infection, and genetic background.
This project will advance our understanding of immunological variation and its significance by studying an immunological model organism in a natural setting. This will ensure that we can both quantify the real extent of immunological variation, why it persists, and its consequences on vaccination and infection.

The heterogeneity between individuals in their immune systems is vast. Understanding the key drivers of immune variation is important as immune trait variability underpins our understanding of disease susceptibility and effectiveness of vaccines. Surprisingly therefore the main drivers of immune variation are poorly defined.
Studies in laboratory mice have contributed to our understanding of the immune system. However they cannot answer questions relating to the relative contribution of heritable and non-heritable factors in shaping the immune system, as they are conducted in controlled conditions with usually just one variable (eg genetics, infection or age).
Using our highly tractable wild mouse population on the Isle of May, where longitudinal analyses of immune responsiveness is possible, we will define the key drivers of immune variation by quantifying functional units of the immune system: cytokines, cell populations and antibody responses, in the context of age, genetics and infection. Specifically we will conduct a cross-sectional study, with groups of mice vaccinated with the model antigen ovalbumin, or sham vaccinated, in the presence or absence of specific infections, and a longitudinal study where we will track immune responses in blood samples over time using a mark, release, recapture protocol. To dissect the contribution of infection to immune variation we will remove key parasite species from a proportion of animals. To dissect the contribution of age to immune variation we will quantify panels of immune markers in blood over time. To understand the contribution of genetics to immune variation we will SNP genotype animals to estimate their relatedness and trait heritability.
By analysing many components of the immune system in the context of heritability, infection and age we will identify how the immune system is shaped. Thus we will define whether the many contributors to immune variability have their basis in heritable or non-heritable factors

Individuals vary in their immune response to infectious disease. Outside of the laboratory, heritable and non-heritable influences combine to impinge on the "decision" as to what sort of immune response ultimately occurs. We do not know how the degree of variability changes as an animal ages and exposures to infectious diseases accumulate. Such variation will have profound effects on the outcome of infectious exposure, to vaccination, and transmission of pathogens.

We do not know the extent of immune variation in wild population of animals; our research will define the main drivers of immune variation in wild mouse populations.

There will thus be a number of impacts as detailed below:

1. Academic community: A wide range of scientists will benefit from our work. Our data will be of interest to immunologists and infectious-disease biologists researching the underlying mechanisms that regulate immunity during health and disease. Epidemiologists and vaccinologists will also benefit from our proposed research as understanding the main drivers of immune variation will inform treatment strategies.

We will ensure our work reaches these varied scientific audiences by publishing our work in both immunology and ecology journals, and by attending national and international conferences, presenting our work orally or via poster. We will also seek to organise Wildlife Immunology focussed sessions at both the British Society for Parasitology and the British Society for Immunology national meetings. (Time frame 1-3 years)

2. General public: Engaging with the public represents our most immediate tangible impact. Our data will be used as a basis for a range of public engagement events achieving educational benefits to the general public. We will develop new activities including a game identifying how immune responses vary with age, infection and genetic makeup. This will increase awareness of the importance of immune responses in the maintenance of health, and the ways scientists carry out basic research with a view to better understanding complex systems.

We will also explain our research project through an exhibit on display in the Visitors centre on the Isle of May. The exhibit will cover not only the concepts behind our research project, focussing on the consequences of immune responses for survival and fitness, but also will tell the story of the Isle of May mice and their unique heritage. The Isle of May is a popular destination for birdwatchers, naturalists and photographers during the Summer months and thus we expect to reach a different group of the general public to the groups who frequently visit for example museums.