Paper Watch : Humans are just pet-store mice …

Two intriguing papers that came out this week suggest that one source of the differences sometimes observed between the immune systems of human and laboratory mice are due to variations in the microbial exposure history of the two hosts.

Laboratory mice have long served as a valuable model for understanding how complex biological systems work (see: introduction to our research). And without the power of this model, our understanding of Immunology, mammalian genetics, cell biology, physiology etc. etc. would be fairly superficial and limited to correlative and/or in vitro observations . However, mice are not humans by any stretch of imagination … And, not surprisingly perhaps, some therapeutic strategies devised using mouse models may not work when applied to human conditions without an intervening layer of optimization for human-mouse differences. The challenge then is to identify the sources of these differences. In the context of the immune system, the two papers below allow us to factor in one such variable – i.e. the multitude of prior microbial exposures that humans have had as opposed to the relatively sterile life that a laboratory mouse lives.

Compared to humans, T cells in lab mice have a relatively “quiet” phenotype with fewer proportions of effector and memory cells. But lymphocytes isolated from mice that were wild-caught (feral) or bought from a local pet store have compositions that mirror those isolated from “wild-caught” humans. Interestingly, subjecting the lab mice to multiple microbial exposures – either using defined microbial pathogens OR just putting them in a cage with mice from a pet store (with all the microbes they carry) – now allows the activated phenotype cells to accumulate in lab mice. Of course, this is only one of many differences between a furry, tailed, 4-legged mammal and a clothed, upright walking, fast-food eating one…. but its an important one.
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References :

  • Beura et al : Normalizing the environment recapitulates adult human immune traits in laboratory mice (Nature 532, p512–516 (28 April 2016))
      Abstract:

    • Our current understanding of immunology was largely defined in laboratory mice, partly because they are inbred and genetically homogeneous, can be genetically manipulated, allow kinetic tissue analyses to be carried out from the onset of disease, and permit the use of tractable disease models. Comparably reductionist experiments are neither technically nor ethically possible in humans. However, there is growing concern that laboratory mice do not reflect relevant aspects of the human immune system, which may account for failures to translate disease treatments from bench to bedside. Laboratory mice live in abnormally hygienic specific pathogen free (SPF) barrier facilities. Here we show that standard laboratory mouse husbandry has profound effects on the immune system and that environmental changes produce mice with immune systems closer to those of adult humans. Laboratory mice–like newborn, but not adult, humans–lack effector-differentiated and mucosally distributed memory T cells. These cell populations were present in free-living barn populations of feral mice and pet store mice with diverse microbial experience, and were induced in laboratory mice after co-housing with pet store mice, suggesting that the environment is involved in the induction of these cells. Altering the living conditions of mice profoundly affected the cellular composition of the innate and adaptive immune systems, resulted in global changes in blood cell gene expression to patterns that more closely reflected the immune signatures of adult humans rather than neonates, altered resistance to infection, and influenced T-cell differentiation in response to a de novo viral infection. These data highlight the effects of environment on the basal immune state and response to infection and suggest that restoring physiological microbial exposure in laboratory mice could provide a relevant tool for modelling immunological events in free-living organisms, including humans.

     

  • Reese et al: Sequential Infection with Common Pathogens Promotes Human-like Immune Gene Expression and Altered Vaccine Response. (Cell Host & Microbe, Volume 19, Issue 5, 11 May 2016, Pages 713–719)
      Abstract:

    • Immune responses differ between laboratory mice and humans. Chronic infection with viruses and parasites are common in humans, but are absent in laboratory mice, and thus represent potential contributors to inter-species differences in immunity. To test this, we sequentially infected laboratory mice with herpesviruses, influenza, and an intestinal helminth and compared their blood immune signatures to mock-infected mice before and after vaccination against yellow fever virus (YFV-17D). Sequential infection altered pre- and post-vaccination gene expression, cytokines, and antibodies in blood. Sequential pathogen exposure induced gene signatures that recapitulated those seen in blood from pet store-raised versus laboratory mice, and adult versus cord blood in humans. Therefore, basal and vaccine-induced murine immune responses are altered by infection with agents common outside of barrier facilities. This raises the possibility that we can improve mouse models of vaccination and immunity by selective microbial exposure of laboratory animals to mimic that of humans.

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