R-spondin 2 signalling mediates susceptibility to fatal infectious diarrhoea

Nat Commun. 2013:4:1898. doi: 10.1038/ncomms2816.

Abstract

Citrobacter rodentium is a natural mouse pathogen widely used as a model for enteropathogenic and enterohemorrhagic Escherichia coli infections in humans. While C. rodentium causes self-limiting colitis in most inbred mouse strains, it induces fatal diarrhoea in susceptible strains. The physiological pathways as well as the genetic determinants leading to susceptibility have remained largely uncharacterized. Here we use a forward genetic approach to identify 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 strains causes a potent Wnt-mediated proliferative response of colonic crypt cells, leading to the generation of an immature and poorly differentiated colonic epithelium with deficiencies in ion-transport components. Our data demonstrate a previously unknown role of R-spondins and Wnt signalling in susceptibility to infectious diarrhoea and identify R-spondin2 as a key molecular link between infection and intestinal homoeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Chromosome Mapping
  • Citrobacter rodentium / physiology*
  • Cloning, Molecular
  • Colon / microbiology
  • Colon / pathology
  • Diarrhea / metabolism*
  • Diarrhea / microbiology*
  • Diarrhea / pathology
  • Disease Susceptibility / metabolism
  • Disease Susceptibility / microbiology*
  • Disease Susceptibility / pathology
  • Enterobacteriaceae Infections / metabolism*
  • Enterobacteriaceae Infections / microbiology
  • Enterobacteriaceae Infections / pathology
  • Epithelial Cells / metabolism
  • Epithelial Cells / microbiology
  • Epithelial Cells / pathology
  • Genetic Association Studies
  • Genetic Loci / genetics
  • Humans
  • Hyperplasia
  • Mice
  • Mice, Inbred Strains
  • Microvilli / microbiology
  • Microvilli / pathology
  • Models, Biological
  • Signal Transduction*
  • Stromal Cells / metabolism
  • Stromal Cells / microbiology
  • Stromal Cells / pathology
  • Survival Analysis
  • Thrombospondins / metabolism*
  • Wnt Signaling Pathway

Substances

  • RSPO2 protein, mouse
  • Thrombospondins