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 diarrhea 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 (Rspo2) as a major determinant of susceptibility to C. rodentium infection. Robust induction of Rspo2 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 signaling in susceptibility to infectious diarrhea and identify Rspo2 as a key molecular link between infection and intestinal homeostasis.

Early colonizing Esche richia coli elicits remodeling of rat colonic epithelium shifting toward a new homeostatic state

“…Citrobacter rodentium infection, which mimics E. coli enteric infections in mice, leads to a highly proliferative and poorly differentiated colonic epithelium due to the downregulation of slc26A3 and CAIV, (another member of the CA family) (Papapietro et al, 2013). Thus, pathogenic and commensal bacteria modulate common targets; however, this process is worsened with pathogenic bacteria, whereas it is balanced with commensal strains with the progressive induction of p21 CIP1 and p27 KIP1 , and Wnt5a.…”

Wnt pathway regulation of intestinal stem cells

“…Rspo2 expression in myofibroblasts increased in response to C. rodentium infection, leading to aberrant proliferation and impaired differentiation of colonic epithelial cells, thus providing evidence that links Rspo proteins to pathophysiological states (Papapietro et al . ). The overlapping expression of Wnts and Rspos within different epithelial and stromal populations of the intestine may enable significant functional redundancy, perhaps to protect from ISC dysfunction and catastrophic loss (Kabiri et al .…”

Citrobacter rodentium -induced colitis: A robust model to study mucosal immune responses in the gut

“…Il12b −/− ++/+++ (Simmons et al, 2002;Zheng et al, 2008) Zheng et al, 2008;Ishigame et al, 2009) (Dann et al, 2008;Basu et al, 2012) Lebeis et al (2009) IL-18 Il18 −/− + ( Lebeis et al, 2009;Liu et al, 2012) Simmons et al, 2002;Shiomi et al, 2010) Goncalves et al, 2001;Fritz et al, 2012) (Lebeis et al, 2007;Gibson et al, 2008a) TLR4 C3H/HeJ, C57BL/10ScNJ ++ (Vallance et al, 2003;Khan et al, 2006 Liu et al, 2012;Nordlander et al, 2014;Song-Zhao et al, 2014;Wlodarska et al, 2014 (Vallance et al, 2003;Willing et al, 2011;Papapietro et al, 2013) …”