title: Helicobacter pylori downregulates expression of human β-defensin 1 in the gastric mucosa in a type IV secretion-dependent fashion.
abstract: Helicobacter pylori establishes a chronic lifelong infection in the human gastric mucosa, which may lead to peptic ulcer disease or gastric adenocarcinoma. The human beta-defensins (hβDs) are antimicrobial peptides, hβD1 being constitutively expressed in the human stomach. We hypothesized that H. pylori may persist, in part, by downregulating gastric hβD1 expression. We measured hβD1 and hβD2 expression in vivo in relation to the presence, density and severity of H. pylori infection, investigated differential effects of H. pylori virulence factors, and studied underlying signalling mechanisms in vitro. Significantly lower hβD1 and higher hβD2 mRNA and protein concentrations were present in gastric biopsies from infected patients. Those patients with higher-level bacterial colonization and inflammation had significantly lower hβD1 expression, but there were no differences in hβD2. H. pylori infection of human gastric epithelial cell lines also downregulated hβD1. Using wild-type strains and isogenic mutants, we showed that a functional cag pathogenicity island-encoded type IV secretion system induced this downregulation. Treatment with chemical inhibitors or siRNA revealed that H. pylori usurped NF-κB signalling to modulate hβD1 expression. These data indicate that H. pylori downregulates hβD1 expression via NF-κB signalling, and suggest that this may promote bacterial survival and persistence in the gastric niche.
authors.affiliation: Nottingham Digestive Diseases Biomedical Research Unit, University of Nottingham, Nottingham, NG7 2RD, UK; Centre for Biomolecular Sciences, University of Nottingham, Nottingham, NG7 2RD, UK.
authors.forename: S R
authors.initials: SR
authors.lastname: Patel
authors.forename: K
authors.initials: K
authors.lastname: Smith
authors.forename: D P
authors.initials: DP
authors.lastname: Letley
authors.forename: K W
authors.initials: KW
authors.lastname: Cook
authors.forename: A A
authors.initials: AA
authors.lastname: Memon
authors.forename: R J M
authors.initials: RJ
authors.lastname: Ingram
authors.forename: E
authors.initials: E
authors.lastname: Staples
authors.forename: S
authors.initials: S
authors.lastname: Backert
authors.forename: A M
authors.initials: AM
authors.lastname: Zaitoun
authors.forename: J C
authors.initials: JC
authors.lastname: Atherton
authors.forename: K
authors.initials: K
authors.lastname: Robinson
mesh_terms: D058947:Bacterial Secretion Systems; D002460:Cell Line; D015536:Down-Regulation; D005753:Gastric Mucosa / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D016481:Helicobacter Infections / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D016480:Helicobacter pylori / Q000276:immunology / Q000378:metabolism* / Q000472:pathogenicity; D006801:Humans; D057131:Immune Evasion / Q000276:immunology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics; D052002:NF-kappa B p50 Subunit / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D015398:Signal Transduction; D013270:Stomach / Q000276:immunology / Q000382:microbiology; D051996:Transcription Factor RelA / Q000235:genetics; D023083:beta-Defensins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D058947:Bacterial Secretion Systems; C406407:DEFB1 protein, human; C106641:DEFB4A protein, human; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; C498143:RELA protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D023083:beta-Defensins; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1