The Trouble with “Clean” Mice: How Infection History Alters Host Immune Responses

Laboratory mice are widely used in biomedical research due to their low cost, genetic tractability, and ease of manipulation. To reduce experimental variability, they are typically housed under specific pathogen-free (SPF) conditions that limit microbial exposure. While this approach minimizes confounding infections, it also creates an immunological environment that differs markedly from that of humans, reducing the translational relevance of mouse immune studies. This limitation has driven the development of alternative models known as "dirty" or microbially experienced (ME) mice. Despite methodological differences, ME models demonstrate that lifelong microbial exposure profoundly shapes immune development. Although immune maturation in these mice is often attributed to microbiome changes, persistent exposure to endemic rodent viruses and other pathogens also may drive sustained immune activation. Here, we review the immune implications of the various ME models and highlight the critical role the virome plays in aligning mouse immune responses more closely with those of humans. Through harnessing microbial experience as a complementary tool to traditional SPF housing conditions and germ-free models, researchers can more faithfully model a mature, pathogen-shaped immune system.