Trends in Immunology
ReviewMaking Mouse Models That Reflect Human Immune Responses
Section snippets
Bystander Infections in Mouse Models
Recent work suggests that specific pathogen-free (SPF) husbandry has broad and unexpected effects on the immune system of mice 1, 2. As their name indicates, SPF mice are free of specific pathogens. The list of organisms tested varies from facility-to-facility and room-to-room, but the organisms usually include both disease-causing pathogens and opportunistic and commensal organisms that do not cause disease in healthy mice. Mice raised in SPF conditions represent the benchmark for studies of
Mice As Model Organisms
The mouse model is the cornerstone of biomedical research. The use of genetically inbred strains reduces variability. Researchers can easily manipulate the mouse genome, especially with the implementation of clustered regularly interspaced short palindromic repeats (CRISPR) technology. Mice are easy to breed and economical to house in animal facilities. Through the use of SPF husbandry, microbial exposures can be controlled, further reducing variability. Experimentation in mice has promoted an
Infection History and Variation in Immune Responses
In humans, interindividual variation in immune responses can be driven by nonheritable influences. In a study of monozygotic twins, it was found that nonheritable factors contribute significantly to variation in cell populations, cytokine responses, and serum proteins between individuals [16]. Moreover, genetically identical twins diverge in immune measurements with age, suggesting that environmental factors drive variation. Within this data set, human cytomegalovirus seropositivity was
Infection Modulates Genetics
Genetic ablation of a gene in mice does not always lead to concordance in phenotype compared with genetic deficiency in humans 21, 22, 23, 24. In many cases, immunodeficient mice are more susceptible to a wide range of infections, whereas genetically deficient humans are susceptible to a smaller subset of pathogens. The question is whether this is actually due to disparate functions of these genes in mice and humans, or whether it is due to differences in nonheritable factors between the two
Does Pathogen Exposure Humanize the Mouse Immune Response?
The data described thus far indicate that altered microbiome, as well as infection with chronic and acute pathogens, change immune responses to unrelated pathogens. Now the question is whether these changes are relevant to the comparison between mice and humans. Do laboratory mice that are infected with a diverse set of pathogens have immune responses more similar to human immune responses (Figure 1)? Two recent studies provide evidence that the answer is yes.
The first study compared the immune
What Is the Normal Microflora of a Mouse?
With the expansion of mouse research there has been a push to make mouse facilities cleaner. We have eliminated many of the pathogens commonly found in laboratory animals and wild rodents. Through sentinel monitoring, mouse rooms are tested routinely for a variety of viral, bacterial, and parasitic pathogens. The pathogens that are routinely monitored depend on the facility and the room. A subset of these pathogens is summarized in Table 1. The impetus behind this is a desire to eliminate
Perspective
If we accept that humans and mice have some level of ongoing infection from a variety of pathogens and commensals, then should we change the way we model disease in mice? We think the answer to this is yes. We described just a few of the examples of mouse ‘pathogens’ that regularly infect wild mice. Given the prevalence of many of these organisms in wild mice, and the fact that they often do not cause disease in immunocompetent mice, these mouse ‘pathogens’ may be more accurately classified as
Concluding Remarks
If we consider the multifarious infection history of humans and compare it with the infection history of laboratory mice, it is clear that the ultra-hygienic environment of experimental mice does not recapitulate the environmental exposures of humans. Work from multiple groups now indicates that infection history changes the mouse immune system, and alters the way in which it responds to challenges. Moreover, increasing a mouse’s infection exposure may enhance correlation between mouse and
Acknowledgments
We thank the Reese Lab for helpful discussion, and Julie Pfeiffer for critical review of the manuscript. T.A.R. is the W.W. Caruth Scholar, Jr. Scholar in Biomedical Research and is supported by the Endowed Scholars program at UTSW.
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