Intestinal epithelial cells display molecular memory weeks post bacterial infection clearance

Studies of mucosal infections have mainly focused on the acute phase at single timepoints, whilst little is known about the host recovery phase. We characterised temporal changes to colonic epithelial cells during the late steady-state, clearance and recovery phases of Citrobacter rodentium infection in C57BL/6 mice. Changes to immuno-metabolism and innate immunity peaked at 10-13 days post infection (DPI) and recovered from 17 DPI. Multiple DNA sensing receptors (ZBP1, STING), pyroptotic (Caspase-1 and -8, GSDMD) and necroptotic (RIPK3, MLKL) proteins were enriched; Ripk3, but not Mlkl, knockout mice presented exacerbated diarrhoea and pathology at 10 DPI. We defined a new “host recovery” phase, characterised by IFN responses and manifested by high abundance of the immunoproteasome and MHC class II subunits, which is unresolved 4 weeks following pathogen clearance. These findings represent a paradigm shift in our understanding of mucosal surfaces recovery from infection.