Integration of multi-omics data from re-wilded laboratory mice to identify key parameters that determine immune heterogeneity and activation

Abstract

Abstract Current research on immunology are largely based on clean laboratory mice kept in specific pathogen free (SPF) environments. They have the advantage of being inbred, genetically homogeneous and can be manipulated genetically in disease models. However, humans as with all free-living mammals face a more complex environment and are exposed to various food resources, microbial experiences, thermogenic changes, and must constantly respond to environmental challenges. We have established a unique experimental system in which laboratory mice are “re-wilded” through release into an outdoor enclosure facility. Here, we use multi-parameter assays including 16S/Metagenomic sequencing, intestinal RNA-sequencing, and 34 parameters of flow cytometry to explain heterogeneity of immune responses from exposure to the wild environment. Increased immune activation of re-wilded mice occur in the absence of viral, bacterial or parasitic pathogen exposure in this enclosure, including increase of CD4+ and CD8+ memory T cells, effector T cells, innate lymphoid cells (ILCs), circulating neutrophils, reduction in naïve T cells, and increased expression of costimulatory molecules on antigen presenting cells. When we examined cytokine production in response to ex vivo stimulation of mesenteric lymph node cells with 8 bacterial and fungal stimuli, the mesenteric lymph node cells from re-wilded mice are poised for different responses via robust induction of cytokines than laboratory mice. By using machine learning models, we are integrating these multi-omic datasets to better predict the association between environmental and host genetic factors on driving heterogeneity of immune responses in the re-wilded mice.