title: Guanylate cyclase C limits systemic dissemination of a murine enteric pathogen.
abstract: BACKGROUND
  Guanylate Cyclase C (GC-C) is an apically-oriented transmembrane receptor that is expressed on epithelial cells of the intestine. Activation of GC-C by the endogenous ligands guanylin or uroguanylin elevates intracellular cGMP and is implicated in intestinal ion secretion, cell proliferation, apoptosis, intestinal barrier function, as well as the susceptibility of the intestine to inflammation. Our aim was to determine if GC-C is required for host defense during infection by the murine enteric pathogen Citrobacter rodentium of the family Enterobacteriacea.
  
  
  METHODS
  GC-C+/+ control mice or those having GC-C genetically ablated (GC-C-/-) were administered C. rodentium by orogastric gavage and analyzed at multiple time points up to post-infection day 20. Commensal bacteria were characterized in uninfected GC-C+/+ and GC-C-/- mice using 16S rRNA PCR analysis.
  
  
  RESULTS
  GC-C-/- mice had an increase in C. rodentium bacterial load in stool relative to GC-C+/+. C. rodentium infection strongly decreased guanylin expression in GC-C+/+ mice and, to an even greater degree, in GC-C-/- animals. Fluorescent tracer studies indicated that mice lacking GC-C, unlike GC-C+/+ animals, had a substantial loss of intestinal barrier function early in the course of infection. Epithelial cell apoptosis was significantly increased in GC-C-/- mice following 10 days of infection and this was associated with increased frequency and numbers of C. rodentium translocation out of the intestine. Infection led to significant liver histopathology in GC-C-/- mice as well as lymphocyte infiltration and elevated cytokine and chemokine expression. Relative to naïve GC-C+/+ mice, the commensal microflora load in uninfected GC-C-/- mice was decreased and bacterial composition was imbalanced and included outgrowth of the Enterobacteriacea family.
  
  
  CONCLUSIONS
  This work demonstrates the novel finding that GC-C signaling is an essential component of host defense during murine enteric infection by reducing bacterial load and preventing systemic dissemination of attaching/effacing-lesion forming bacterial pathogens such as C. rodentium.
authors.affiliation: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA. Kris.Steinbrecher@cchmc.org.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Mann
authors.forename: Eleana
authors.initials: E
authors.lastname: Harmel-Laws
authors.forename: Mitchell B
authors.initials: MB
authors.lastname: Cohen
authors.forename: Kris A
authors.initials: KA
authors.lastname: Steinbrecher
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D058491:Bacterial Load; D018988:Bacterial Translocation / Q000502:physiology; D044082:Citrobacter rodentium / Q000502:physiology; D003106:Colon / Q000276:immunology* / Q000473:pathology; D004756:Enterobacteriaceae Infections / Q000235:genetics / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology; D008099:Liver / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled / Q000235:genetics / Q000276:immunology*; D018000:Receptors, Peptide / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D018000:Receptors, Peptide; C000613655:Gucy2c protein, mouse; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled