Research: Lab Mice not like Wild Mice not like Humans

The comparative immunology of wild and laboratory mice, Mus musculus domesticus : Nature Communications – May 2017

Though this article focuses on the immune system, it exposes differences that could definitely have implications for pain research as well.

Of course, using any animal to study our pain makes no sense, since our pain is supposedly a bio-psycho-social disorder, with the focus mostly on “catastrophizing”. I’m not sure mice can do that or how it could be measured.

Wild mice are immunologically different from laboratory mice. Serological and morphometric parameters for the wild (HW) and laboratory (C57/BL6) mice are summarized in Table 1 (see below). The wild mice were much smaller than the laboratory mice (weighing only half as much)

From 62 immunological measures most (57 measures) differed between wild and laboratory mice.Among the wild mice there were very few (6 of 62 measures) significant immunological differences between male and female mice, while the laboratory mice were more (18 of 62 measures) immunologically sexually dimorphic.

Multilocus genotyping shows that the HW wild mice are an unstructured, genetically diverse population. The wild mice are genetically distinct from ten laboratory mouse strains, and the laboratory strains are more genetically diverse than are the wild mice.We suggest that this genetic relationship between the wild and laboratory mice is explained by the mosaicisim of laboratory mouse genomes, by the fact that laboratory mice have been deliberately separated from each other for many generations, and by the fact that laboratory strains are largely homozygous.

Wild mice carry a substantial burden of infection

The laboratory mouse is the workhorse of immunology, used as a model of mammalian immune function, but how well immune responses of laboratory mice reflect those of free-living animals is unknown. Here we comprehensively characterize serological, cellular and functional immune parameters of wild mice and compare them with laboratory mice, finding that wild mouse cellular immune systems are, comparatively, in a highly activated (primed) state.

Infection of wild mice was very common: all wild mice had been infected with at least one pathogen and only 5% (8 of 153) were seronegative for all the viruses and M. pulmonis. There was no effect of sex on the intensity or prevalence of infection.

Wild mice have very high concentrations of serum proteins

Associations between immune parameters and infection suggest that high level pathogen exposure drives this activation. Moreover, wild mice have a population of highly activated myeloid cells not present in laboratory mice.

In wild mice, serum concentrations of IgG and IgE were 20- and 200-fold higher, respectively, in wild mice than in the laboratory mice.

Wild mice also had significantly higher serum concentrations of the acute phase proteins, serum amyloid P component (SAP) and haptoglobin than laboratory mice.

By contrast, in vitro cytokine responses to pathogen-associated ligands are generally lower in cells from wild mice, probably reflecting the importance of maintaining immune homeostasis in the face of intense antigenic challenge in the wild. These data provide a comprehensive basis for validating (or not) laboratory mice as a useful and relevant immunological model system.

Wild mice were more heterogeneous in their concentrations of immunoglobulins and acute phase proteins compared with laboratory mice.

Introduction

Most of our understanding of the mammalian immune system comes from detailed studies of inbred, laboratory-adapted strains of the house mouse, Mus musculus domesticus, but whether such responses are indicative of those of free-living, outbred populations is unknown

Laboratory mice have been genetically isolated from their free-living relatives for more than 80 years such that laboratory strains capture only a small part of the genetic variation present in wild populations

Laboratory mouse strains are also mostly genetically homozygous often resulting in phenotypes caused by recessive alleles. Indeed, major differences exist among inbred mouse strains in immune phenotype and function, and resistance or susceptibility to infectious or inflammatory diseases. Many of these traits have been mapped to specific loss of function mutations in genes that affect the immune response

The different genetic heritage of wild and laboratory mice is obvious in other ways given that laboratory mice are larger and heavier than, and differ in coat colour from, wild M. musculus domesticus. In adaptation to the laboratory, mice have been selected for rapid growth, early maturation, high fecundity and docility and inadvertent selection for immunological traits is almost certain.

Equally important for immune function, laboratory mice typically live in highly controlled and optimized environments, have unlimited access to food and are kept free of pathogens; the increasing trend towards housing animals in individually ventilated cages further reduces exposure to environmental antigens

By contrast, wild mice are continually exposed to environmental antigens, are typically infected by numerous microparasites and macroparasites, and face competition for resources (for example, food, mates, safe nesting places). Wild mouse populations are subject to continual selection in this very different antigenic and physical environment, where immune responses make an important contribution to their fitness.

Given these substantial differences between wild and laboratory animals and their respective environments, differences between their baseline immune parameters, immune responses to model antigens and functional immune competence are expected. Understanding immune phenotype and function in wild mice is essential for understanding immune responses of genetically diverse, free-living populations, including humans

Although immune function might be assumed to differ between wild and laboratory mice, this assumption is based on remarkably little empirical evidence; there are only four published reports of the immune function of wild M. musculus domesticus.

Although these studies support the idea that wild and laboratory mice differ immunologically, the lack of an extensive, immune system-wide analysis of populations of wild mice tempers this conclusion. It therefore remains the case that the immune responses of wild mice are essentially unknown and thus that the validity of laboratory mice as a model immunological system is uncertain.

We have therefore undertaken a detailed phenotypic and functional analysis of the immune systems of 460 wild mice (M. musculus domesticus) from 12 sites in the southern UK,

Results

  • Wild mouse splenocytes differ from those of laboratory mice
  • Wild mice have a hitherto unknown myeloid cell population
  • Wild mouse NK cells are highly activated
  • Wild mice have reduced cytokine responses to PAMPs

Discussion

Laboratory mice are the mainstay of experimental immunology and underpin work that has had a transformative effect on human and animal lives through vaccination and, more recently, immunotherapy

As the human population ages, understanding immune-mediated disease and immunosenescence is of ever increasing importance

For laboratory mice to be useful in understanding these processes, and for treatments and therapies to be effectively translated into human populations, we need to appreciate both the strengths and limitations of the model.

Given that the ultimate purpose of the immune system is to provide protection from external environmental threats, the environment in which the immune system is studied is a priori likely to have profound effects on its response.

This uniquely extensive and detailed immune characterization of wild mice shows that their immune systems are highly activated and antigen-experienced, likely because wild mice are continuously exposed to high levels of environmental antigenic challenge, have high levels of infection and high cumulative exposure to infection over their, often remarkably short, lives

By complete contrast, innate immune function—as measured by cytokine secretion in response to pathogen-associated ligands—is remarkably similar between highly infected wild mice and pathogen-free laboratory mice and, where there are differences, the responses of wild mice are suppressed.

It is also notable that we have identified a novel cell population in wild mice—which we have termed hypergranulocytic myeloid cells—that are apparently absent from laboratory mice

The status of the immune systems of wild and laboratory mice therefore appears very different. Our data are consistent with the immune systems of wild mice dynamically responding to a large and ever changing diversity of antigens: wild mice seem to be constantly immunologically multi-tasking. In contrast, laboratory mice are likely responding to a very limited antigenic repertoire, allowing greater immunological focus.

The immune response observed in a laboratory mouse is thus just one example of the myriad immune responses that can be generated by outbred, free-living individuals. Considerable caution should therefore be exercised in extrapolating results from laboratory mice to free-living animals and human populations.

Laboratory mice are ultimately derived from wild mice, but have been subject to stringent selection during their laboratory history which has, presumably, altered them in many ways. It is likely that selection of laboratory mice for a range of life-history traits (such as rapid growth and reproduction, and docility) has resulted in alteration of a range of traits, including immunological traits. This makes the important point that animals’ immune responses need to be considered as one aspect of their wider range of life-history traits, and truly understanding wild animals’ immune responses therefore needs to be embedded within the wider context of their life-history biology

While much more remains to be done to fully understand immune function in free living populations, these data provide a sound basis for future studies on wild Mus musculus domesticus. Most importantly, the marked among-individual heterogeneity of immune parameters in wild mice provides a rich resource for disentangling associations between genotype, environment and phenotype, and how the immune response contributes to evolutionary fitness.

Supplementary Figure and Supplementary Tables

PDF files

Excel files

Table 1: The body characteristics and serum protein concentrations of wild mice and their comparison to laboratory mice. (https://www.nature.com/articles/ncomms14811/tables/1)

From: The comparative immunology of wild and laboratory mice, Mus musculus domesticus

Statistical results show comparisons between sex within animal source (that is, laboratory or wild mice), and between animal source.

Where there exists a significant difference between sex, mice were grouped by sex and animal source as: laboratory female, laboratory male, wild female and wild male (LF, LM, WF, WM, respectively), with Kruskal–Wallis H-tests (and post hoc, Dunn–Bonferonni, pairwise comparisons) conducted with significant differences reported.

Where data were normal (that is, body length, body mass and spleen mass: body mass ratio) or could be transformed to normal (log10 transformation of age; untransformed data shown), the results of univariate GLMs are reported. All non-normal data were analysed by Mann–Whitney U-tests, unless stated otherwise.

Asterisks denote significant differences as *P<0.05, **P<0.01, ***P<0.001

Table 2: Characterization of natural killer cell populations of wild mice and their comparison to laboratory mice.
(https://www.nature.com/articles/ncomms14811/tables/2)

From: The comparative immunology of wild and laboratory mice, Mus musculus domesticus

Statistical results show comparisons between sex within animal source (that is, laboratory or wild mice), and between animal source.

Where there exists a significant difference between sex, mice were grouped by sex and animal source as: laboratory female, laboratory male, wild female and wild male (LF, LM, WF, WM, respectively), with Kruskal–Wallis H-tests (and post hoc, Dunn–Bonferonni, pairwise comparisons) conducted with significant differences reported. All non-normal data were analysed by Mann–Whitney U-tests, unless stated otherwise.

Asterisks denote significant differences as *P<0.05, **P<0.01, ***P<0.001. Superscripts define cell populations as a percentage of: 1spleen cells; 2NK cells.

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