title: R-spondin 2 signalling mediates susceptibility to fatal infectious diarrhoea.
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.
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada H3A 2B4.
authors.forename: Olivier
authors.initials: O
authors.lastname: Papapietro
authors.forename: Sarah
authors.initials: S
authors.lastname: Teatero
authors.forename: Ajitha
authors.initials: A
authors.lastname: Thanabalasuriar
authors.forename: Kyoko E
authors.initials: KE
authors.lastname: Yuki
authors.forename: Eduardo
authors.initials: E
authors.lastname: Diez
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.forename: Eugene
authors.initials: E
authors.lastname: Kang
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dhillon
authors.forename: Aleixo M
authors.initials: AM
authors.lastname: Muise
authors.forename: Yves
authors.initials: Y
authors.lastname: Durocher
authors.forename: Martin M
authors.initials: MM
authors.lastname: Marcinkiewicz
authors.forename: Danielle
authors.initials: D
authors.lastname: Malo
authors.forename: Samantha
authors.initials: S
authors.lastname: Gruenheid
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002874:Chromosome Mapping; D044082:Citrobacter rodentium / Q000502:physiology*; D003001:Cloning, Molecular; D003106:Colon / Q000382:microbiology / Q000473:pathology; D003967:Diarrhea / Q000378:metabolism* / Q000382:microbiology* / Q000473:pathology; D004198:Disease Susceptibility / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D004756:Enterobacteriaceae Infections / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D056726:Genetic Association Studies; D056426:Genetic Loci / Q000235:genetics; D006801:Humans; D006965:Hyperplasia; D051379:Mice; D008815:Mice, Inbred Strains; D008871:Microvilli / Q000382:microbiology / Q000473:pathology; D008954:Models, Biological; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D016019:Survival Analysis; D019699:Thrombospondins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D000098907:R-Spondins
chemical_list: D019699:Thrombospondins; C518904:RSPO2 protein, mouse; D000098907:R-Spondins