Dirty mice are the next revolution in immunology research

Fig1_DirtyMice_SLVMay2016
Credit: Martyn Fletcher via Flickr

Laboratory mice are one of the most valuable tools scientists rely on to understand how pathologies work. In order to find a cure for a disease, we need to have comprehensive knowledge of the physiological processes which are impaired. For instance, we can manipulate mice genetically to assess the effect of either the deletion, overexpression or even modification of proteins leading to a pathophysiological state. We can also select strains which share common features to known diseases as models amenable to pharmacological intervention. This is a major advantage because as mammals, they recapitulate the complex link between different physiological systems, allowing to measure the impact of the disease at the cardiovascular, renal or neurological level, for instance. Furthermore, they can reproduce fast and are quite easy to handle and maintain, without the needs of a large amount of space.

However, there are limitations imposed by the necessity of keeping them in pathogen-free barrier facilities (SPF), in addition to the fact they have been systematically inbred, aiming to avoid as much genetic variability as possible. Certainly one of the main ones relates to immunology research undertaken in these mice because such studies are often not directly translatable into humans. This is not surprising as the extreme hygienic conditions they live in result in a lack of certain populations of immune cells that need exposure to pathogens in order to mature and strengthen the immune response. As a consequence, many promising therapies fail in late clinical stages because of the lack of well-founded preclinical data. It is indeed precise but within the wrong context. Being scientists aware of such constraints, no meaningful alternatives have been explored to date.

Recently, the group of David Masopust at the University of Minnesota decided to test an unusual but clever idea. They wanted to know what would happen to ‘immunologically inexperienced‘ mice when forced to be housed with common wild ‘dirty’ mice 12. As a starting point, they compared the immune system of laboratory mice to that of humans, realizing that it is closely related to the one from the neonatal human. As we have mentioned, these mice lack a population of highly specialized cells called CD8+-T memory cells, responsible to quickly and effectively respond to pathogens the organism has been previously infected by. This is somehow expected, as they have not been exposure to barely any pathogen throughout their lives. Furthermore, they confirmed this difference was not a common hallmark found in all rodents, but specific to laboratory mice. Analysis of the immune system from both living-free barn and pet store commercial mice showed an antigen-experienced CD8+-T cell pattern much closer to adult humans than laboratory mice.

They decided then to co-house ‘dirty’ and laboratory mice to dissect the genetic and environmental components of such immunological differences. Not surprisingly, the laboratory mice had a tough time with 22% of them dying within eight weeks of being together. However, the remaining ones were able to survive increasing their CD8+ peripheral blood mononuclear cells (PBMCs) count from 15% to 70% in just four weeks. Exposure to different pathogens such as virus, bacteria and helminth could also be confirmed. Thus, mice co-housing leads to a fast development of effector and memory T cells matching that of ‘dirty’ mice and adult humans. Those changes were not just limited to T cells but also to the levels of antibodies, being significantly increased in serum. The observed changes meant that co-housed laboratory mice could fight more effectively infection than non-exposed mice. This conclusion came after comparing the reduction in bacterial concentration after inoculating both mice types (co-housed vs non-exposed) with Listeria monocytogenes, a common pathogen used in research to determine the immune status in laboratory mice. Co-housed mice bacterial load was comparable to that of vaccinated mice against that specific pathogen.

To further substantiate their results, they evaluated the genetic expression pattern from pet-store or co-housed PBMCs along with laboratory mice PBMCs and compare them to the ones from either adult or neonate humans. To do so, they used data from a previous study in which cell samples were collected from umbilical cord from newborns and their mothers, looking for transcriptome alterations in the new-borns as a consequence of tobacco smoking. The transcriptome comprises the whole set of messenger RNA the organism, giving an idea about which genes are being transcribed and therefore, active. Comparison of the top 400 genes upregulated in pet and co-housed mice matched the upregulated ones in the adult human, while the top 400 downregulated ones were enriched in both neonates and laboratory mice. This result suggests that laboratory mice can quickly switch their immune-related gene expression program from neonate to adult in few weeks after being exposed to ‘dirty’ mice. All in all, their conclusions suggest that adding ‘immunologically trained’ laboratory mice to the repertoire of research tools would be beneficial to study immune-related pathologies. Of course, that does not mean SPF mice should not be used anymore because it is not uncommon breeding immunosuppressed mice in areas of research such as cancer or stem cell biology, and these mice must be kept in a pathogen-free environment or they would die otherwise.

One could argue after looking at these encouraging results, scientists should immediately switch to these mice when working in the development of therapies aiming to target immunology-related diseases. Unfortunately, this will not be straightforward. Mice suppliers will decide whether to implement all the necessary facilities and breeding programs based on whether they can make a profit out of them. In addition, the vast majority of mice facilities would not allow housing these mice because they might infect the whole mice colony which is likely not meant for similar studies. So new dedicated facilities will have to be built, again with the financial burden that implies. For now, if somebody is interested in them, at least they can get in touch with Masopust´s lab as they have indeed set-up a co-housing facility suitable for these mice, with the intention of arranging collaboration agreements (2). Hopefully, this will be the tip of a gigantic iceberg in a near future.

References

  1. Beura LK, Hamilton SE, Bi K, Schenkel JM, Odumade OA, Casey KA, Thompson EA, Fraser KA, Rosato PC, Filali-Mouhim A, Sekaly RP, Jenkins MK, Vezys V, Haining WN, Jameson SC, Masopust D. Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature. 2016 Apr 28;532(7600):512-6. doi: 10.1038/nature17655.
  2. Reardon S. Dirty room-mates make lab mice more useful. Nature. 2016 Apr 21;532(7599):294-5. doi: 10.1038/532294a.

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