A single cell and spatially resolved atlas of the intestinal innate immune response to infection 2266151

Abstract

Abstract Introduction Advances in single cell technologies have uncovered novel biology and revealed cellular heterogeneity of complex tissues. However, single cell resolution data for the distal small intestine - a critical site of nutrient absorption and immunological tolerance - are limited, particular during states of infection or inflammation. Methods We generated GUTMAP, a single cell transcriptional atlas of more than 500k cells, from ileum and draining lymph node to address this need and provide a community resource for the study and annotation of intestinal data. Multiple established models of intestinal infection were profiled at acute immunological timepoints to catalogue innate responses to diverse pathogens including SFB, Nippostrongylus brasiliensis, Candida albicans, Yersinia pseudotuberculosis, Cryptosporidium parvum, and murine norovirus. To complement these data and integrate transcriptional responses with tissue pathology, we also carried out single cell spatially resolved transcriptomics. Results Using GUTMAP, we compare between infections and resolve 91 transcriptional cell states in the ileum, including infection-driven and pathogen-specific transcriptional modules. We describe unique enterocyte biology associated with Yersinia infection and demonstrate a spatial link between enterocyte phenotype and the formation of pyogranulomas during infection. We further probe the spatially coordinated cell networks and trafficking during diverse responses to reveal conserved patterns in immune architecture across infection systems. Conclusion GUTMAP is a resource for mucosal immunologists that captures single cell biology of the ileum across diverse infections to answer pivotal questions about innate immune biology. Additionally, GUTMAP acts as resource and bioinformatic tool to aid in the annotation of mucosal data sets and a foundational support for future studies of inflammatory dysregulation in the small intestine. Funding Source NIAID - U01AI095608 Topic Categories Mucosal and Regional Immunology (MUC)