Comparison of mouse models of microbial experience reveals differences in microbial diversity and response to vaccination

Specific pathogen-free (SPF) laboratory mice dominate preclinical studiesfor immunology and vaccinology. Unfortunately, SPF mice often fail to accurately modelhuman responses to vaccination and other immunological perturbations. Several groupshave taken different approaches to introduce additional microbial experience to SPFmice to better model human immune experience. How these different models compare is unknown. Here, we directly compare three models: housing SPF mice in amicrobe-rich barn-like environment (feralizing), adding wild-caught mice to the barn-likeenvironment (fer-cohoused), or cohousing SPF mice with pet store mice in a barrierfacility (pet-cohoused); the two latter representing different murine sources of microbialtransmission. Pet-cohousing mice resulted in the greatest microbial exposure. Feralizingalone did not result in the transmission of any pathogens tested, while fer-cohousingresulted in the transmission of several picornaviruses. Murine astrovirus 2, the mostcommon pathogen from pet store mice, was absent from the other two model systems. Previously, we had shown that pet-cohousing reduced the antibody response tovaccination compared with SPF mice. This was not recapitulated in either the feralized orfer-cohoused mice. These data indicate that not all dirty mouse models are equivalentin either microbial experience or immune responses to vaccination. These disparitiessuggest that more cross model comparisons are needed but also represent opportunities to uncover microbe combination-specific phenotypes and develop more refinedexperimental models. Given the breadth of microbes encountered by humans across theglobe, multiple model systems may be needed to accurately recapitulate heterogenoushuman immune responses.