The immune system is shaped throughout life by many variables such as diet, and infection history, yet most of our immunological knowledge stems from controlled laboratory experiments that strive to eliminate the variation which will be at play in natural environments. Here, Dr Iris Mair and Professor Kathryn Else introduce the fascinating emerging field of ecoimmunology, which draws from both ecology and immunology to explore how the immune system functions in the real world.
A 5-week long fieldtrip to a remote Scottish island – the Isle of May – is not quite considered standard laboratory practice in the immunology community. But we hope it will become a celebrated new tool in the toolbox of immunological research going forward, connecting the immunology community with the ecology community for an enhanced understanding of what shapes the immune system in a complex, uncontrolled environment.
So, what is special about the Isle of May? It is home to a feral population of house mice, Mus musculus domesticus – the same species as laboratory mice. This mouse population has historically been studied in the context of genetics and population ecology. With a 40% recapture rate within one month, the Isle of May mice lend themselves to mark-release–recapture studies. This means immune responses can be monitored within an individual over time. This is especially important given that mounting any immune response needs to integrate with the rest of an animal’s physiology and so will vary with, for example, reproductive status, social interactions and environmental stressors. Such a tractable wild mouse system also offers the opportunity of performing interventional studies in a real-world context with the full analytical power of the laboratory mouse immunology.
Exploring the noise around immune variation
Ecoimmunology combines the seemingly opposing strengths of population/disease ecology and immunology. While ecologists explore the uncontrolled variation seen within a population with the aim to uncover broad associations, immunologists aim to control the experimental variable(s) to understand cellular and molecular mechanisms at play within an individual. There are good reasons why reductionist approaches have been adopted in immunology. By using genetically identical, inbred strains of mice for example, controlling for sex, age and environment, the amount of experimental ‘noise’ is minimised and results are more reproducible. What if, however, we want to understand what induces this noise, i.e. immune variation? Humans are inherently diverse in genetic makeup as well as ‘life-history traits’, as ecologists term the ‘age- and stage-specific patterns, and timing of events that together make up an organism's life’. Immunologists, whether clinical or pre-clinical, will invariably ask the question of: why do individuals react so differently to the same immunological challenge? Which environmental or host-associated factors determine the immune response? In order to bridge between the immense knowledge from controlled laboratory experiments, and the uncontrolled environment animals and humans live in, ecoimmunology has emerged over the past decades with the hope to accelerate translational research, whether for public health, animal welfare or conservation purposes.
Such a tractable wild mouse system also offers the opportunity of performing interventional studies in a real-world context with the full analytical power of the laboratory mouse immunology.
‘Dirty’ lab mice as a more human-like model system
The laboratory mouse has been the most used immunological model for human health and disease, and has led to incredible discoveries. However, the immune system of inbred laboratory mice resembles more closely that of a newborn than that of an adult human; this is due to a lack of exposure to normal life-history events and a less controlled environment. We call a mouse without intervention ‘naïve’, and it is true for its immune system too. ‘Dirtying up’ laboratory mice simply by co-housing them with mice from a pet shop, allowing the microbiomes to transmit, results in a significantly more mature immune system, resembling more the immune makeup of an adult human. An elegant study by Barbara Rehermann’s group tested drugs which had failed in clinical trials due to safety concerns in naïve laboratory mice (in which these drugs had been deemed safe in pre-clinical trials), and in ‘wildling’ lab mice with microbiomes from wild mice. The ‘wildlings’ reacted with similar adverse effects as seen in human volunteers, and so could have served as a warning sign in previous pre-clinical studies.
This study highlights that we may be able to render the laboratory mouse model system more relevant to translational science, and thereby increase the efficacy of pre-clinical research, by integrating ‘re-wilded’ lab mouse set-ups into our translational pipeline. Taking this approach one step closer to the real-world complexity, Andrea Graham’s group have set up outdoor enclosures to release laboratory mice – of specific age, sex, genotype and intervention – into a semi-wild environment. This allows the tight control of certain host factors while allowing variation in other factors such as microbial exposure, diet, exercise, social contacts and weather. Through this set-up, it has become apparent that a change of environment can make the difference between a mouse being susceptible or resistant to parasite infection.
Going wild for immunology
The immunological study of fully wild animals, including the Isle of May mice, offers one step further in the aim to embrace complexity, by a priori allowing all natural variation to be at play. Wild immunology approaches need not just focus on Mus musculus. Indeed, important findings have been made in wild populations of non-model organisms including wild sheep, voles, wood mice and buffalo. However, for immunologists, wild house mice are a key enabling factor in the study of immunology. Our tools available for the dissection of immune responses are vast, matched only in human immunology research which of course represents another wild system but with less opportunity for interventional studies.
Using flow cytometry to phenotype the immune cells present in several organs in wild house mice, our own as well as other groups were able to show that wild mice have a much more mature immune system than laboratory naïve mice, as suggested by the ‘dirty’ lab mouse models. Further, we saw immune cell ratios and phenotypes rarely described in laboratory settings in relevant immunological organs such as spleen, peripheral lymph nodes and bone marrow. It will be fascinating to learn what the drivers behind these are and the functional consequences of these naturally occurring phenotypes. Given that maintaining immune cells and mounting immune responses are costly, in a natural setting where several physiological processes compete and trade-offs are likely, we hypothesise that there are functional benefits for these phenotypes. Not just cell phenotype, but cytokine responses to a parasitic infection – Trichuris muris – were distinct in wild mice compared with laboratory mice.
Validating our controlled laboratory models in a relevant natural context is one of the benefits of ecoimmunological research. For example, in collaborative work across lab mice, wild mice and humans, we were able to assert whether differences in findings across lab mice and humans is likely due to the controlled environment, or a species-specific difference. Given the required permits, it is also possible to do interventional studies in wild mice, getting at mechanism: we are currently pioneering immunological interventions in the wild mice and are using wild-to-lab microbiome transfers to dissect the interplay between diet, the immune response and the microbiome in determining susceptibility to endoparasitic infection. Our work also speaks strongly to the 3Rs agenda with our approach involving harvesting multiple tissues from each individual mouse, creating a ‘biobank’ of material accompanied by rich metadata suitable for future exploration.
Challenges and future directions
Due to its interdisciplinary and exploratory nature, ecoimmunology comes with challenges, especially as the area establishes itself, with ‘gold-standards’ yet to be defined. Especially for immunologists, one of the greatest challenges lies in the integration of fieldwork into the experimental design. Scarce availability of tools and assays for non-model organisms can limit the immunological detail. One way of circumventing this issue is of course the use of model organisms and introducing real-world variation in a controlled (laboratory), semi-controlled (enclosures, zoos) or uncontrolled (wild population) setting, as exemplified above. Not every immunologist has access to wild animal systems or the legislation in place to allow their study. However, everyone can take steps towards developing systems which explore real-world immunology by being mindful of context and introducing multiple variables into their study systems such as sex, age, genetic background or previous infection.
We are currently pioneering immunological interventions in the wild mice and are using wild-to-lab microbiome transfers to dissect the interplay between diet, the immune response and the microbiome in determining susceptibility to endoparasitic infection.
Continued growth of this interdisciplinary area requires immunologists and ecologists alike to learn each other’s language, to engage in conversation around best practice and a drive to expose students and researchers to a broad spectrum of research approaches and learn from each other. This transcends the engagement ladder from teaching curriculum, meetings and conferences, interdisciplinary funding calls, and journals’ openness to publishing papers crossing the boundaries between these two research arenas.
Our upcoming Special Collection on ecoimmunology in the BSI’s journal Discovery Immunology aims to provide a publishing home for research in this interdisciplinary area, spanning from humans to non-model organisms and laboratory immunology to ecological field studies. Keep an eye on the journal’s website and Twitter/X page to read the the latest articles in the collection as soon as they are published.
Ecoimmunology encourages a bridging of two research arenas which are ultimately concerned with individual and population health. We encourage you to consider the context in which your immunological research ultimately plays out, and hope that ecoimmunology can help to generate new discoveries about how the immune system functions in, and interacts with, the natural world.
Dr Iris Mair, University of Edinburgh
Professor Kathryn Else, University of Manchester
Coming soon: Ecoimmunology Special Collection
Led by Dr Iris Mair & Professor Kathryn Else
In this upcoming Special Collection, Discovery Immunology welcomes original research and reviews addressing a range of topics pertinent to the field of ecoimmunology, including:
- Ecological drivers of immune responses in wild animals
- Naturalising laboratory immunology models
- Human immunology: holistic studies
- Computational and/or statistical advances in working with ecoimmunological data sets
- Novel immunological insights or applications in non-model species
Your submission will form part of a novel, ongoing collection, aiming to provide a publishing home for research in this interdisciplinary research area, spanning from humans to non-model organisms and laboratory immunology to ecological field studies.
Submissions for this series are welcome throughout 2024. For more information on submitting your paper, go to the journal's website or please contact our editorial office at journals@immunology.org.