R-Spondin 2 signalling mediates susceptibilityto fatal infectious diarrhoea

摘要

Citrobacter rodentium is a natural mouse pathogen widely used as a model for enteropathogenicand enterohemorrhagic Escherichia coli infections in humans. While C. rodentium causesself-limiting colitis in most inbred mouse strains, it induces fatal diarrhoea in susceptiblestrains. The physiological pathways as well as the genetic determinants leading to susceptibilityhave remained largely uncharacterized. Here we use a forward genetic approach toidentify the R-spondin2 gene as a major determinant of susceptibility to C. rodentium infection.Robust induction of R-spondin2 expression during infection in susceptible mouse strainscauses a potent Wnt-mediated proliferative response of colonic crypt cells, leading to thegeneration of an immature and poorly differentiated colonic epithelium with deficiencies inion-transport components. Our data demonstrate a previously unknown role of R-spondinsand Wnt signalling in susceptibility to infectious diarrhoea and identify R-spondin2 as a keymolecular link between infection and intestinal homoeostasis.