title: Dual ligand/receptor interactions activate urothelial defenses against uropathogenic E. coli.
abstract: During urinary tract infection (UTI), the second most common bacterial infection, dynamic interactions take place between uropathogenic E. coli (UPEC) and host urothelial cells. While significant strides have been made in the identification of the virulence factors of UPEC, our understanding of how the urothelial cells mobilize innate defenses against the invading UPEC remains rudimentary. Here we show that mouse urothelium responds to the adhesion of type 1-fimbriated UPEC by rapidly activating the canonical NF-κB selectively in terminally differentiated, superficial (umbrella) cells. This activation depends on a dual ligand/receptor system, one between FimH adhesin and uroplakin Ia and another between lipopolysaccharide and Toll-like receptor 4. When activated, all the nuclei (up to 11) of a multinucleated umbrella cell are affected, leading to significant amplification of proinflammatory signals. Intermediate and basal cells of the urothelium undergo NF-κB activation only if the umbrella cells are detached or if the UPEC persistently express type 1-fimbriae. Inhibition of NF-κB prevents the urothelium from clearing the intracellular bacterial communities, leading to prolonged bladder colonization by UPEC. Based on these data, we propose a model of dual ligand/receptor system in innate urothelial defenses against UPEC.
authors.affiliation: Department of Urology, New York University School of Medicine.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University, UM2, Institut National de la Santé et de la Recherche Médicale (Inserm), U1104 and Centre National de la Recherche Scientifique (CNRS) UMR7280, Marseille, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mémet
authors.affiliation: Research and Postgraduation of University Anhembi Morumbi, S. Paulo, SP 03164-000, Brazil.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Saban
authors.affiliation: Departments of Biochemistry and Molecular Pharmacology, New York University School of Medicine.
authors.forename: Xiangpeng
authors.initials: X
authors.lastname: Kong
authors.affiliation: University of Washington, Seattle, WA 98195.
authors.forename: Pavel
authors.initials: P
authors.lastname: Aprikian
authors.affiliation: University of Washington, Seattle, WA 98195.
authors.forename: Evgeni
authors.initials: E
authors.lastname: Sokurenko
authors.affiliation: Department of Urology, New York University School of Medicine.|Departments of Biochemistry and Molecular Pharmacology, New York University School of Medicine.|Departments of Cell Biology, New York University School of Medicine.|Departments of Dermatology, New York University School of Medicine.
authors.forename: Tung-Tien
authors.initials: TT
authors.lastname: Sun
authors.affiliation: Department of Urology, New York University School of Medicine.|Department of Pathology, New York University School of Medicine.|Departments of Veterans Affairs New York Harbor Healthcare System, Manhattan Campus, New York, NY 10010.
authors.forename: Xue-Ru
authors.initials: XR
authors.lastname: Wu
mesh_terms: D018830:Adhesins, Escherichia coli / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001422:Bacterial Adhesion / Q000235:genetics; D036781:Fimbriae Proteins / Q000096:biosynthesis* / Q000235:genetics; D015964:Gene Expression Regulation, Bacterial; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D008024:Ligands; D008070:Lipopolysaccharides / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014552:Urinary Tract Infections / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D056689:Uropathogenic Escherichia coli / Q000235:genetics* / Q000472:pathogenicity; D060167:Uroplakin Ia / Q000235:genetics / Q000378:metabolism*; D019459:Urothelium / Q000378:metabolism / Q000382:microbiology / Q000473:pathology
chemical_list: D018830:Adhesins, Escherichia coli; D008024:Ligands; D008070:Lipopolysaccharides; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D060167:Uroplakin Ia; C058769:fimH protein, E coli; D036781:Fimbriae Proteins