Viney, M., Lazarou, L., & Abolins, S. (2015). The laboratory mouse andwild immunology. Parasite Immunology, 37(5), 267-73. DOI:10.1111/pim.12150

Publisher's PDF, also known as Version of record

License (if available):CC BY

Link to published version (if available):10.1111/pim.12150

Link to publication record in Explore Bristol ResearchPDF-document

This is the final published version of the article (version of record). It first appeared online via Wiley athttp://dx.doi.org/10.1111/pim.12150. Please refer to any applicable terms of use of the publisher.

University of Bristol - Explore Bristol ResearchGeneral rights

This document is made available in accordance with publisher policies. Please cite only the publishedversion using the reference above. Full terms of use are available:http://www.bristol.ac.uk/pure/about/ebr-terms

Review Article

The laboratory mouse and wild immunology

M. VINEY, L. LAZAROU & S. ABOLINS

School of Biological Sciences, University of Bristol, Bristol, UK

SUMMARY

The laboratory mouse, Mus musculus domesticus, has beenthe workhorse of the very successful laboratory study ofmammalian immunology. These studies – discovering howthe mammalian immune system can work – have allowed thedevelopment of the field of wild immunology that is seekingto understand how the immune responses of wild animalscontributes to animals’ fitness. Remarkably, there havehardly been any studies of the immunology of wild M. mus-culus domesticus (or of rats, another common laboratorymodel), but the general finding is that these wild animalsare more immunologically responsive, compared with theirlaboratory domesticated comparators. This difference proba-bly reflects the comparatively greater previous exposure toantigens of these wild-caught animals. There are now excel-lent prospects for laboratory mouse immunology to makemajor advances in the field of wild immunology.

Keywords ecoimmunology, fitness, Mus, wild

THE LABORATORY MOUSE ANDIMMUNOLOGY

The laboratory mouse – Mus (Mus) musculus domesticusto give it its full name – is the unsung hero of biology.Generation upon generation of such mice have been usedin almost every conceivable aspect of biological research.In the same way that animals used in our wars receivemedals for bravery, the laboratory mouse should beawarded an honorary Nobel Prize for its contribution toscience. Mice have particularly been used in the study ofgenetics and immunology and their use in immunologicalresearch continues to grow. Their scientific utility is that

they are mammals and so closely related to ourselves.Their practical attractiveness is that they are small, easyto keep, and breed rapidly.Laboratory mouse immunology has been hugely success-

ful at discovering and understanding the working networkof the mammalian immune system. Using animals fromdefined genetic stocks, in tightly controlled environments,with ever more complex immune manipulations (includinggenetic manipulations and knockouts, etc.), this work hasdiscovered the bewilderingly complex functioning of themouse immune system. This has been a triumph of areductionist biology approach to understand a complexsystem. The nascent field of ecoimmunology or wild immu-nology only exists because of the fundamental, reduction-ist-based approach to mammalian immunology. It is onlyby knowing how the immune system of a laboratory mouse(and hence other mammals and vertebrates) works thatone can even conceive sensible questions of wild animals’immune lives. Laboratory-based mouse immunology tellsus what the mouse immune system can do and how it canfunction. But, it has also taught us that the functioning ofthe host immune response is utterly context dependent, sothat the context of wild animals will profoundly affect theirimmune function. Wild immunology is therefore trying tounderstand how an animal’s ecology affects its immunefunction. This is then the next step for immunology, some-thing that started with the laboratory mouse.

TAXONOMY, WILD ORIGINS ANDLABORATORY DOMESTICATION

Mus musculus domesticus is widespread throughout theworld, now encompassing northern Europe, the Americas,Africa and Australasia, usually living commensally withpeople. Other subspecies have a more restricted range, forexample with M. musculus musculus in northern Eurasia,M. musculus casteneus in south-east Asia and M. musculusbactrianus in India (1). These four subspecies are well rec-ognized although recent genetic evidence continues to

Correspondence: Mark Viney, School of Biological Sciences, Uni-versity of Bristol, Bristol BS8 1TQ, UK (e-mail: mark.viney@bris-tol.ac.uk).Disclosures: None.Received: 30 May 2014Accepted for publication: 3 October 2014

© 2014 The Authors. Parasite Immunology published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License,which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

267

Parasite Immunology, 2015, 37, 267–273 DOI: 10.1111/pim.12150

reveal further complexity (e.g. 2, 3); some authorities rec-ognize M. musculus and M. domesticus as species, ratherthan subspecies of M. musculus (4). There is an apparentlystable hybrid zone in central Europe between M. musculusdomesticus to the west and M. musculus musculus to theeast. At least in one part of this zone the M. musculusdomesticus alleles are more able to introgress than those ofM. musculus musculus (5).The inbred strains of mice commonly used in the labo-

ratory (such as C57BL/6, BALB/c) originated from the1920s onwards with animals taken from the fancy mousetrade and thus come from mixed, but limited, sources (1).The sequencing of the genome of laboratory mice (specifi-cally of C57BL/6) confirmed this mixed ancestry (6) show-ing that its genome was mosaic. Thus, about two-thirds ofthe genome has a low level of polymorphism with otherlaboratory strains, while the remaining third is highlypolymorphic compared with other laboratory strains (6).Thus, when comparing C57BL/6 with another laboratorystrain, in the low polymorphism regions both strainsappear to have inherited this region from the same subspe-cies, be it from M. musculus domesticus or from M. mus-culus musculus. In contrast, across the high polymorphismregions, each strain seems to have inherited this regionfrom a different one of these two subspecies (6). Thismeans that the laboratory mouse is not a simple domesti-cated version of M. musculus domesticus, but a segmentedmuddle of M. musculus domesticus and M. musculusmusculus, at least.In the almost 100 years since some of the most com-

monly used laboratory strains were established, there havebeen various efforts to incorporate more of wild mousegenetics into strains available for laboratory use (1). Vari-ous wild-derived inbred strains have been made based onanimals trapped in various parts of the world (from Asia,central Europe to the Americas), many of which are there-fore other subspecies of M. musculus. These wild-derivedinbred strains have been used in genetic mapping (for bothimmunological and nonimmunological traits), includingvia F1 hybrids made by crosses to already existing strains,such as C57BL/6. Because these wild-derived inbredstrains are genetically distinct from the existing laboratoryinbred strains, and because the existing inbred strains havea mosaic genome (above), these derived F1 hybrids havevery substantial genetic diversity available that can be usedin genetic mapping (7).Clearly, mice have been selected while being domesti-

cated to the laboratory, as has any other domesticated spe-cies. This process started with the mice used in the pettrade and then continued in laboratory mice. Laboratorymice will principally have been selected to be good (highand rapid fecundity) breeders, which itself will have

selected on a whole suite of life-history and physiological,etc. traits. The mouse immune system and its function areunlikely to have been left unselected during this process.Comparison of the food intake, growth rates, etc. of wild-caught mice (at least three generations post-capture) andlaboratory mice showed that the wild-derived female miceate less food, grew more slowly and became sexuallymature later (by approximately 3 weeks) than laboratorymice (8). The male wild mice also grew less quickly thanthe laboratory mice, but they reproductively matured atthe same rate (8). These findings are consistent with labo-ratory mice, especially females, having been selected tofeed rapidly so as to grow and reproduce quickly.

ECOLOGY

Wild M. musculus domesticus is most commonly knownliving commensally with humans, typically in farm outbuildings etc. Such populations can be very stable, proba-bly because of the constant availability of food (9) – manysmall mammals eat approximately half their body weightin food everyday (10). Beyond the absolute availability offood, a mouse’s position in an environment can alsosignificantly alter its behaviour, with ecological conse-quences (11). Animals in these stable, commensal popula-tions rarely move beyond where they are born (except viaaccidental, passive human action), so that only a verysmall proportion of mice will move more than 25 m intheir life – young male mice are those most likely to dis-perse (12). Within such an environment there are a mosaicof male-defended territories, with each reinforced byurine-derived cues (9, 13). In each territory there is onedominant male, a few subordinate males, several breedingfemales and some of their offspring (9). Mice can poten-tially breed continuously (9), but within each territoryreproduction is manipulated by signalling among the micevia pheromones in their urine. Firstly, females’ ovulation iscontrolled by these pheromones – cues from males acceler-ate ovulation, and cues from females slow ovulation (9).Females’ puberty is also affected by cues from otherfemales (9), and male hormone titres are themselvesaltered in response to female urine. What all this means isthat the reproductive biology of mice within a territory iscontrolled by these multiple interindividual interactionsthat effectively temporally control female ovulation andalso male reproductive-cueing behaviour (9).Mice can also live feral in free-living habitats and in

these settings they generally live at much lower densities,their positions are less stable, individual’s home rangesmay be much larger, and more dispersion occurs (9, 12).Much less is known about the social structuring of micein these settings, but it is probably unlikely that the stable,

268 © 2014 The Authors. Parasite Immunology published by John Wiley & Sons Ltd., Parasite Immunology, 37, 267–273

M. Viney et al. Parasite Immunology

or semi-stable, demic structure (above) occurs because theferal populations are much less stable (9). Indeed, in thesepopulations monthly mortality has been estimated at 30%,with 90% mortality over winter (9). Even within commen-sal populations it has been estimated that about half of allmice born do not join the adult population after weaning(13). A survey of the age structure of wild-caught com-mensal mice showed that most male mice were less than28 weeks old (the very oldest male mouse was 62 weeksold); female mice often lived to be older with them com-monly reaching 60 weeks of age (the oldest female mousewas almost 100 weeks old) (14).For mice in either commensal or feral settings they all

have to contend with infection from a variety of patho-gens. Several studies have surveyed populations of wildmice for the prevalence of a range of infections (15–17).In many cases the sought-for infections have occurred ata high prevalence (suggesting that these wild mice maybe reservoirs of infection for laboratory mice) (16), butthe effect of these infections in wild mice themselves isnot well understood. Comparing these studies also showsthat the infections also differ among mouse populations.For example, serological surveys for infection with Sendaivirus among wild mice in the north of England (15),Pennsylvania, USA (16), and Thevenard Island, Australia(18) found no evidence of infection, while in south-eastern Australia there was a prevalence of 1�8% (19). Inour own study of wild mice from across southern Eng-land and Wales between 2012 and 2014 we found a Sen-dai virus seroprevalence of 51%. More generally, in oursurvey of eight different infections, we have found thatmice are exposed to multiple infections from early in lifesuch that no mouse was infection-free after 5 weeks ofage, and that by 4 weeks of age (the approximate time ofweaning) most mice had three or four different infec-tions.For infection with the pinworm Syphacia spp. preva-

lence of infection also varies substantially among popula-tions (20), ranging from 2% in the UK (21) to 67% inAustralia (22); we have observed a prevalence of 71% forSyphacia spp. among most of our sampled mice, thoughan absence of this in mice from Skokholm Island, Wales,and from the London Underground.

THE WILD IMMUNOLOGY OF MUSMUSCULUS DOMESTICUS

There has been very limited study – in fact just threepapers – of the immune function of wild M. musculusdomesticus. The very first comparison of wild-caught mice(as well as of other wild-caught rodent species) that werethen maintained in the laboratory, with laboratory-bred

mice, immunized the animals with sheep red blood cells(SRBC) and then assayed the in vitro lysis of SRBC bysplenocytes from the immunized animals (23). This foundthat the wild mice caused significantly greater SRBC lysiscompared with the laboratory mice (23). In a secondstudy, a comparison of wild-caught (then laboratory main-tained) mice with a standard laboratory mouse strainshowed that in response to immunization with keyholelimpet haemocyanin (KLH) the wild-caught mice weregenerally more immune reactive, as shown by greater andmore avid anti-KLH antibody responses (24). The wild-caught animals’ splenic leucocytes also showed a greateroverall activation (measured by flow cytometric analysis),compared with those of the standard laboratory mice (24).In both these studies the wild-caught mice presumably hadthese immune phenotypes because of the antigenic chal-lenges that they had had before they were caught, some-thing that had not happened to the laboratory strains ofmice. There was a very notable degree of interindividualvariation in the immune measures among the wild mice,more so than among the laboratory mice (23, 24). Thesedifferences were also likely to be due to genetic differencesamong mice and due to their different prior history (anti-genic history, infection, health status, etc.). In the thirdstudy, natural killer (NK) cells of wild-caught mice (thatwere then maintained in the laboratory for no more than7 days) and of laboratory strains of mice were compared(25). This found that the wild-caught mice had NK cellsin the peripheral lymph nodes (but the laboratory micedid not) and that the NK cells of the wild-caught micewere in a primed state, compared with those from labora-tory mouse strains (25). Further, when the NK cells werestimulated with cytokines the wild-caught mouse NK cellsresponded to a comparatively greater extent (25). Asabove, this difference between mice from these two sourceswas probably because the wild-caught mice had beenunder sustained microbial exposure during their wild lives,unlike their laboratory-bred, effectively na€ıve counterparts(25). Together, these three studies show that, perhaps notsurprisingly, wild-caught mice have qualitatively differentmeasures of immune function compared with laboratorystrains of mice, probably due to the different antigenicexposure histories of the mice from these two sources. Theimmune system responds to antigen and so wild animals,with their richer antigenic history, will have immune sys-tems that are in a different state than that of na€ıve, labora-tory-bred animals. There was also very substantialvariance among the wild animals in their immunologicalmeasures, with this both due to the animals differinggenetically and in their prior antigenic history, physiologi-cal state, etc., factors that are largely standardized amongthe laboratory-bred mice.

© 2014 The Authors. Parasite Immunology published by John Wiley & Sons Ltd., Parasite Immunology, 37, 267–273 269

Volume 37, Number 5, May 2015 The laboratory mouse and wild immunology

There has also been some analysis of the immune func-tion of wild-derived inbred strains of mice (above). Thesestrains differ in phenotypes of immunological interest,both when compared with each other and when comparedwith established laboratory mouse strains. For example,among wild-derived inbred mouse strains some are com-paratively hyporesponsive to stimulation with polyino-sinic–polycytidylic acid (poly(I:C)) [measured as thetumour necrosis factor a (TNFa) produced by peritonealmacrophages following in vitro stimulation] compared withC57BL/6, but generally not following stimulation withother molecules such as lipopolysaccharide (LPS), pepti-doglycan, CpG, etc. (26). This difference was trackeddown to the effect of a different allele of the TLR3-codinglocus of the hyporesponsive strains, compared with the“normally” responsive strains (26). Some wild-derivedinbred mouse strains also showed a resistance to the effectof LPS administration, something that kills C57BL/6 mice(27). This gross phenotypic difference has an immunologi-cal basis because the wild-derived mice that were resistantto the effect of LPS administration were comparativelydeficient in their macrophages’ production of interferon b(IFN-b). The origin of this effect was complex, appearingto be under polygenic control (27). Also, among otherwild-derived (but not inbred) mouse strains there was adiversity of B cell responsiveness (but not of macrophageresponsiveness), such that some of the wild-derived strainswere significantly less responsive than the laboratory strainC57BL/6, while other wild-derived strains were similar tothe laboratory strain (28).Using these wild-derived inbred strains of mice will

principally reveal the effects of genetic differences amongthe mice, be these simple one-locus effects, or more com-plex effects. Because these wild-derived inbred strainsinclude a number of subspecies of M. musculus then this ispotentially revealing genetic effects beyond M. musculusdomesticus itself. Moreover, what these studies show is therather self-evident fact that the immune phenotype ofstandard laboratory strains of mice (such as C57BL/6) isjust one phenotype from a range of many possibilities.Perhaps inevitably, much of this literature takes it as self-evident that the immune response of the standard labora-tory strain is normal and that of the wild-derived mice isreduced or defective (26), but this of course does not rec-ognize that the standard laboratory mouse and its pheno-type is just one sample of what exists in the wild.A number of studies have investigated the genetic diver-

sity of wild mice, specifically of genes of immunologicalrelevance (e.g. 29, 30). These often report variants, or lev-els of diversity, that are surprising from the perspective oflaboratory strains of mice, but often the deeper signifi-cance and broader relevance of this genetic diversity and

of its functional immunological effect is less clear.However, the approach used in (30) is particularly interest-ing from a wild immunology perspective. Specifically, inthis study different genetic variants in the regulatoryregion of the Fcgr2b gene in wild mice were found, andthe most common wild haplotype was then knocked intoC57BL/6 mice (30). This knocked-in mouse strain wasthen used to make detailed study of the molecular geneticand immunological effect of this particular haplotype. Thisapproach was therefore able to go from identifying geno-types in wild mice to assaying their functional effect in thelaboratory.

RATS – RATTUS NORVEGICUS ANDSIGMODON HISPIDUS – AN ASIDE

Rats are also common laboratory animals whose immu-nology has also been studied in the laboratory. Analo-gously there has also been some study of the immunefunction of wild rats. Wild rats (R. norvegicus) had greaterserum concentrations of IgG, IgM and IgE, comparedwith laboratory-bred rats, and there were more autoreac-tive IgG antibodies in wild rats, compared with laboratoryrats (31). In contrast to the studies with wild mice showingthat wild animals were often more immunologicallyresponsive compared with laboratory animals (above), wildrat splenocytes were less responsive to stimulation withConA, compared with laboratory-derived rat splenocytes,by a number of measures; the exception was the produc-tion of interleukin 4 (IL-4), which was significantly greaterby stimulated splenocytes of wild rats compared withthose of laboratory-bred rats (32). Flow cytometric analy-sis of cells from wild and from laboratory-bred ratsshowed a number of differences, but of note was that thewild-caught rats had a comparatively greater measure ofactivation of their T cells (33). In general the rather fewstudies of wild R. norvegicus show that the wild rats differimmunologically from laboratory strains of rats, withmany of these differences also probably due to the previ-ous infection and antigenic exposure of the wild animals,compared with the laboratory strains of rats.In wild-caught cotton rats, S. hispidus, comparisons of

measures of humoral and cellular immune functionthroughout the year showed seasonal changes in thesemeasures, with this possibly being due to density-dependent effects operating within the sampled population(34). In this study there were no laboratory-bred, controlanimals against which the wild-caught animals could becompared (34). In many species it has been shown that anindividual’s diet can have profound effects on measures ofimmune function (35). When wild-caught S. hispidus weremaintained in enclosures with different (both quantitative and

270 © 2014 The Authors. Parasite Immunology published by John Wiley & Sons Ltd., Parasite Immunology, 37, 267–273

M. Viney et al. Parasite Immunology

qualitative) feeding regimes, better-quality food increased thetotal number of white blood cells, as well as some other hae-matological values (36), suggesting that some aspects of theimmune function of these cotton rats were limited by theirnatural environment.Considering these studies of wild mice and of wild rats

together, firstly it is remarkable how very, very few stud-ies there have been. Secondly, the measures of theimmune responses of the wild animals are recognisablysimilar to those of laboratory strains. Thirdly, wild ani-mals differ immunologically from the laboratory animalsin ways that are probably due to the wild animals havinghad a history of sustained antigenic exposure – some-thing completely consistent with their wild lives. Fourth,there is significant interindividual immunological varia-tion among the wild animals, which could be due togenetic differences and prior-environmental differencesamong individuals.

THE CENTRAL QUESTIONS OF WILDIMMUNOLOGY

The central question of wild immunology is how doesan animal’s immune system and its immune responsescontribute to that animal’s fitness (35, 37, 38)? Becausethe immune system and its consequent responses is justone of many physiological systems of an animal, thisquestion can never be divorced from asking how otheraspects of an animal’s life – for example, physiologicalinvestment in reproduction – also contribute to its fit-ness. Because these and other physiological processesrequire resources, and because it is thought that animalsare often resource limited, then animals have difficultdecisions of resource allocation to make, with the conse-quence that the immune response mounted is often doneso under these conditions of resource limitation (35).Thus, our starting question can be refined to what arethe optimal immune responses that an animal shouldmake to maximize its fitness? Here, the answer may becounterintuitive, for example that some hyporesponsive-ness is optimal because (i) this might avoid immuno-pathological effects and (ii) that by not responding thenlimited resources are available for something else (37).Individual animal’s lives differ in many ways and there-fore what is immunologically optimal will be individualspecific. Moreover, because prior functioning of theimmune system affects its future function, then this candrive very substantial immunological differences amongindividuals. This therefore means that questions of wildimmunology need to ask about the functional effect ofthe immune system rather more than measurement ofdetailed immunological parameters.

IMMUNOLOGY’S NEXT MAJOR CHALLENGE

It is time for the laboratory mouse to get back to the field.The decades of immunological research on mice and thevast repertoire of tools and reagents can – and should –

be used in wild immunology. Laboratory-based, reduction-ist mouse immunology has been working towards this end,for all these years, without realizing what its destiny wouldbe. What sort of studies can, and should, now be done?Clearly the style of study possible in a laboratory and thatpossible in the field is different, but the challenges ofworking in the field are not insurmountable hurdles. Ironi-cally, much mouse-based immunological work is carriedout with the perspective of understanding human immu-nology, and in these settings researchers continually movebetween laboratory-based studies of mice and field-basedstudies of humans. It is obviously possible to make immu-nological observations of wild mice that we could not ofhumans, so the wild immunology study of wild mice ispotentially easier than integrated human–mouse studies.Laboratory-based immunology has explained how the

immune system works – that is the networks of signals,checks and balances that define what immunological out-put results from what antigenic and immunological input.These basic mechanisms are not then what needs to berestudied per se in wild animals. We need to find out whatis the standard immunological background of wild mice,and we need to redefine normal to wild mice and so stopapplying this label to laboratory mice. What we need toknow for wild mice is what is the functional immunologi-cal output of a mouse in its environment, and what is theeffect of this output on its ecology and fitness. This is ahard problem of ecology, not necessarily a hard problemof immunology.These studies are possible and tractable now. The per-

fect study would be a longitudinal one of marked wild ani-mals, but where an animal’s capture and sampling israndom. This has been done very successfully with othersmall rodent systems (e.g. 39). At each sample we wouldthen want to know what sort of immune responses theanimal is making, including both general measures but,with more refined hypotheses, understanding antigen-spe-cific responses would also be key. Repeating this over ananimal’s short life (hence using sample collection that isnon-lethal) would enable a summary of each mouse’simmunological life-history course to be described. For theecology and fitness, at each capture we will want to knowabout its relative success (thus measuring survival andhealth, etc.). Reproductive success is the key measure offitness, and here genetics can be used to measure individu-als’ genetic contribution to succeeding generations. Inessence, this is what the long-running study of the St Kilda

© 2014 The Authors. Parasite Immunology published by John Wiley & Sons Ltd., Parasite Immunology, 37, 267–273 271

Volume 37, Number 5, May 2015 The laboratory mouse and wild immunology

Soay sheep has done, so that this has generated a verygood understanding of what contributes to a sheep’sfitness on St Kilda (40). Wild mouse systems, though,offer considerably greater analytical power both becausethe necessary immunological characterization is very muchmore straightforward and because replicate populationscan be used with wild mice. The ability to replicate studypopulations gives very substantial statistical advantages,but it also allows the opportunity to understand how dif-ferent geographies and ecologies affect how mice use theirimmune responses.So far we have considered the two extremes – the labo-

ratory and the wild – but a halfway house of enclosures ispossible too. These have the advantage that there aredefined animals within the enclosures that, in theory, canbe caught and sampled at will (41). The enclosures can beleft semi-wild or managed in various ways to perturb thetest population. Of course such enclosures allow replica-tion and the use of different treatments. A different typeof halfway house is the approach used in (30), wheregenetic variants of wild mice are knocked-in to laboratorymouse strains for laboratory assay.So far, such studies of either truly wild populations or

of enclosed, semi-wild animals are observational studies,but in both settings the populations can be manipulatedto test specific hypotheses. This is where the immunologi-cal power of the laboratory mouse can be used for verygreat effect. Many of the immune manipulations that arestandardly used in laboratory immunology can in princi-ple be used with wild animals. This means that some cellpopulations can be depleted, or supplemented; that cer-tain cytokines or other signalling molecules can be inhib-ited and that the effect on mice, their ecology and fitnesstested. Clearly these would be nontrivial wild experi-ments, but they would be very powerful experiments.What these approaches would allow is the test of thefunctional effect of immune system components in a real-world context.

MOUSE GENETICS

Currently large international research consortia are tryingto discover the function of all of the mouse genes. Thisis being done by systematically knocking out genes andthen phenotyping the animals in many ways. Mouseknockouts have been used very extensively in immunolog-ical research, allowing researchers to disentangle theeffects of different cell types and molecules on immuneresponses and other phenotypes. All this is being done tounderstand how genes control immunological phenotypes.In the wild there are several, complementary ways in

which wild mouse immunogenetics could be studied.Firstly, taking inspiration from human-based genomewide association studies (GWAS), traits of immunologicalinterest could be genetically mapped in wild mice. Simply,wild mice are caught, their relevant immune phenotype ismeasured, the mice genotyped, and then associationssought between the trait and genotype. This approach ispotentially hugely powerful, explaining the genomicarchitecture underlying the trait in question. The resultsmay be complex, because of epistatic and pleiotropiceffects. Further, results may differ among different mousepopulations [thus highlighting environmental (E), genetic(G) and also G 9 E effects]. However, this complexity iswhat needs to be embraced. While the one gene, onephenotype paradigm is attractive and tractable, within-genome interactions are as important and complex asthose within a mammalian immune system. GWAS-styleanalysis of wild mice populations is a powerful way todiscover the genetic control of immunological traits inthe ecological context of a mouse and its immuneresponse. Such analyses can continually move betweenthe field and the laboratory.These analyses can go a next step too. The relative suc-

cess of different alleles at loci of immunological interestcan be followed in wild populations. This could be a studyof already existing allelic diversity in the study popula-tions. Alternatively, alleles present in laboratory strainscould be introgressed into wild mice and then released intothe wild (or, at least, enclosures) and their populationgenetic success, as well as the immunological and ecologi-cal effect studied in the wild.The possibilities of what could be done to understand

how the mouse immune system is functioning in wild pop-ulations, and the effect of this function on the ecology andfitness of wild mice, are endless. For inspiration we shouldturn to the genome-enabled field biology approach that iscurrently being used with plants (42). This major pro-gramme of work is genetically dissecting and manipulatingtraits in real-world conditions. By manipulating a traitgenetically and phenotypically and then testing the conse-quent effects on fitness in the organism’s natural environ-ment the challenge of modern biology is addressed headon: this is what laboratory mouse wild immunology cannow do.

ACKNOWLEDGEMENTS

MV would like to thank NERC, the Wellcome Trust andthe Leverhulme Trust for funding. We would like to thankMichael Pocock for comments on a previous version ofthis manuscript.

272 © 2014 The Authors. Parasite Immunology published by John Wiley & Sons Ltd., Parasite Immunology, 37, 267–273

M. Viney et al. Parasite Immunology

REFERENCES

1 Silver LM. Mouse Genetics. Concepts andApplications. Oxford, OUP, 1995: 362.

2 Lundrigan BL, Jansa SA & Tucker PK. Phy-logenetic relationships in the genus Mus,based on paternally, maternally, and biparen-tally inherited characters. Syst Biol 2002; 51:410–431.

3 Suzuki H, Nunome M, Kinoshita G, et al.Evolutionary and dispersal history of Eur-asian house mice Mus musculus clarified bymore extensive geographic sampling of mito-chondrial DNA. Heredity 2013; 111: 375–390.

4 Berry RJ & Scriven PN. The house mouse: amodel and motor for evolutionary under-standing. Biol J Linn Soc 2005; 84: 335–347.

5 Raufaste N, Orth A, Belkhir K, et al. Infer-ences of selection and migration in the Dan-ish house mouse hybrid zone. Biol J LinnSoc 2005; 84: 593–616.

6 Wade CM, Kulbokas EJ, Kirby AW, et al.The mosaic structure of variation in the lab-oratory mouse genome. Nature 2002; 420:574–578.

7 Ideraabdullah FY, Casa-Esper�on E, Bell TA,et al. Genetic and haplotype diversity amongwild-derived mouse inbred strains. GenomeRes 2004; 14: 1880–1887.

8 Bronson FH. Energy allocation and repro-ductive development in wild and domestichouse mice. Biol Reprod 1984; 31: 83–88.

9 Bronson FH. The reproductive ecologyof the house mouse. Q Rev Biol 1979; 54:265–299.

10 Speakman J. Factors influencing the dailyenergy expenditure of small mammals. ProcNutr Soc 1997; 56: 1119–1136.

11 Stueck KL & Barrett GW. Effects ofresource partitioning on the populationdynamics and energy utilization strategies offeral house mice (Mus musculus) populationsunder experimental field conditions. Ecology1978; 59: 539–551.

12 Pocock MJO, Hauffe HC & Searle JB. Dis-persal in house mice. Biol J Linn Soc 2005;84: 565–583.

13 Berry RJ & Bronson FH. Life-history andbioeconomy of the house mouse. Biol Rev1992; 67: 519–550.

14 Rowe FP, Bradfield A, Quy RJ & SwinneyT. Relationship between eye lens weight andage in the wild house mouse (Mus musculus).J Appl Ecol 1985; 22: 55–61.

15 Becker SD, Bennett M, Stewart JP & HurstJL. Serological survey of virus infectionamong wild mice (Mus domesticus) in theUK. Lab Anim 2007; 41: 229–238.

16 Parker SE, Malone S, Bunte RM & SmithAL. Infectious diseases in wild mice (Musmusculus) collected on and around the Uni-versity of Pennsylvania (Philadelphia) cam-pus. Comp Med 2009; 59: 424–430.

17 Murphy RG, Williams RW, Hughes JM,Hide G, Ford NJ & Oldbury DJ. The urbanhouse mouse (Mus domesticus) as a reservoirof infection for the human parasite Toxo-plasma gondii: an unrecognised public healthissue. Int J Environ Health Res 2008; 18:177–185.

18 Moro D, Lloyd ML, Smith AL, Shellam GR& Lawson MA. Murine viruses in an islandpopulation of introduced house mice andendemic short-tailed mice in Western Austra-lia. J Wildl Dis 1999; 35: 301–310.

19 Smith AL, Singleton GR, Hansen GM &Shellam G. A serologic survey for virusesand Mycoplasma pulmonis among wild housemice (Mus domesticus) in south-eastern Aus-tralia. J Wildl Dis 1993; 29: 219–229.

20 Tattersall FH, Nowell F & Smith RH. Areview of the endoparasites of wild housemice Mus domesticus. Mamm Rev 1994; 24:61–71.

21 Behnke JM & Wakelin D. The survival ofTrichuris muris in wild populations ofits natural hosts. Parasitology 1973; 67: 157–164.

22 Singleton GR. Population dynamics of Musmusculus and its parasites in Mallee wheat-lands in Victoria during and after a drought.Aust Wildlife Res 1985; 12: 437–445.

23 Lochmiller RL, Vestey MR & McMurrayST. Primary immune responses of selectedsmall mammal species to heterologous ery-throcytes. Comp Biochem Physiol A 1991;100: 139–143.

24 Abolins SR, Pocock MJO, Hafalla JCR,Riley EM & Viney ME. Measures ofimmune function of wild mice, Mus muscu-lus. Mol Ecol 2011; 20: 881–892.

25 Boysen P, Eide DM & Storset AK. Naturalkiller cells in free-living Mus musculus have aprimed phenotype. Mol Ecol 2011; 20: 5103–5110.

26 Stephan K, Smirnova I, Jacque B & Polto-rak A. Genetic analysis of the innateimmune responses in wild-derived inbredstrains of mice. Eur J Immunol 2007; 37:212–223.

27 Mahieu T, Park JM, Revets H, et al. Thewild-derived inbred mouse strain SPRET/Eiis resistant to LPS and defective in IFN-bproduction. Proc Natl Acad Sci USA 2006;103: 2292–2297.

28 Thiriot A, Drapier AM, M�emet S, et al.Wild-derived mouse strains, a valuable modelto study B cell responses. Mol Immunol2009; 46: 601–612.

29 Scalzo AA, Manzur M, Forbeds CA, BrownMG & Shellman GR. NK gene complexhaplotype variability and host resistancealleles to murine cytomegalovirus in wildmouse populations. Immunol Cell Biol 2005;83: 144–149.

30 Espeli M, Clatworthy MR, B€okers S, et al.Analysis of a wild mouse promoter variantreveals a novel role for FccRIIb in the con-trol of the germinal center and autoimmuni-ty. J Exp Med 2012; 209: 2307–2319.

31 Devalapalli AP, Lesher A, Shieh K, et al.Increased levels of IgE and autoreactive,polyreactive IgG in wild rodents: implica-tions for the hygiene hypothesis. ScandJ Immunol 2006; 64: 125–136.

32 Lesher A, Li B, Whitt P, et al. Increased IL-4 production and attenuated proliferativeand pro-inflammatory responses of spleno-cytes from wild-caught rats (Rattus norvegi-cus). Immunol Cell Biol 2006; 84: 374–382.

33 Trama AM, Holzknecht ZE, Thomas AD,et al. Lymphocyte phenotypes in wild-caughtrats suggest potential mechanisms underlyingincreased immune sensitivity in post-indus-trial environments. Cell Mol Immunol 2012;9: 163–174.

34 Lochmiller RL, Vestey MR & McMurrayST. Temporal variation in humoral and cell-mediated immune response in a Sigmodon hi-spidus population. Ecology 1994; 75: 236–245.

35 Viney ME & Riley EM. From Immunologyto Eco-immunology: More than a NewName. In Malagoli D, Ottaviani E (eds):Eco-Immunology: Evolutive Aspects andFuture Perspectives. London, Springer, 2014:1–19.

36 Webb RE, Leslie DM, Lochmiller RL &Masters RE. Immune function and hematol-ogy of male cottons rats (Sigmodon hispidus)in response to food supplementation andmethionine. Comp Biochem Physiol A MolIntegr Physiol 2003; 136: 577–589.

37 Viney ME, Riley EM & Buchanan KL.Optimal immune responses: immunocompe-tence revisited. Trends Ecol Evol 2005; 20:665–669.

38 Pedersen AB & Babayan SA. Wild immunol-ogy. Mol Ecol 2011; 20: 872–880.

39 Telfer S, Lambin X, Birtles R, et al. Speciesinteractions in a parasite community driveinfection risk in a wildlife population. Sci-ence 2010; 330: 243–246.

40 Clutton-Brock TH & Pemberton JM. SoaySheep: Dynamics and Selection in an IslandPopulation. Cambridge, CUP, 2004: 383.

41 Stockley P, Ramm SA, Sherborne A, ThomM, Paterson S & Hurst JL. Baculum mor-phology predicts reproductive success ofmale house mice under sexual selection.BMC Biol 2013; 11: 66.

42 Baldwin IT. Training a new generation ofbiologists: the genome-enabled field biolo-gists. Proc Am Philos Soc 2009; 156:205–214.

© 2014 The Authors. Parasite Immunology published by John Wiley & Sons Ltd., Parasite Immunology, 37, 267–273 273

Volume 37, Number 5, May 2015 The laboratory mouse and wild immunology