title: Helicobacter pylori exploits cholesterol-rich microdomains for induction of NF-kappaB-dependent responses and peptidoglycan delivery in epithelial cells.
abstract: Infection with Helicobacter pylori cag pathogenicity island (cagPAI)-positive strains is associated with more destructive tissue damage and an increased risk of severe disease. The cagPAI encodes a type IV secretion system (TFSS) that delivers the bacterial effector molecules CagA and peptidoglycan into the host cell cytoplasm, thereby inducing responses in host cells. It was previously shown that interactions between CagL, present on the TFSS pilus, and host α(5)β(1) integrin molecules were critical for CagA translocation and the induction of cytoskeletal rearrangements in epithelial cells. As the α(5)β(1) integrin is found in cholesterol-rich microdomains (known as lipid rafts), we hypothesized that these domains may also be involved in the induction of proinflammatory responses mediated by NOD1 recognition of H. pylori peptidoglycan. Indeed, not only did methyl-β-cyclodextrin depletion of cholesterol from cultured epithelial cells have a significant effect on the levels of NF-κB and interleukin-8 (IL-8) responses induced by H. pylori bacteria with an intact TFSS (P < 0.05), but it also interfered with TFSS-mediated peptidoglycan delivery to cells. Both of these effects could be restored by cholesterol replenishment of the cells. Furthermore, we demonstrated for the first time the involvement of α(5)β(1) integrin in the induction of proinflammatory responses by H. pylori. Taking the results together, we propose that α(5)β(1) integrin, which is associated with cholesterol-rich microdomains at the host cell surface, is required for NOD1 recognition of peptidoglycan and subsequent induction of NF-κB-dependent responses to H. pylori. These data implicate cholesterol-rich microdomains as a novel platform for TFSS-dependent delivery of bacterial products to cytosolic pathogen recognition molecules.
authors: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
authors: Melanie L
authors: ML
authors: Hutton
authors: Maria
authors: M
authors: Kaparakis-Liaskos
authors: Lorinda
authors: L
authors: Turner
authors: Ana
authors: A
authors: Cardona
authors: Terry
authors: T
authors: Kwok
authors: Richard L
authors: RL
authors: Ferrero
mesh_terms: D000942:Antigens, Bacterial / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000276:immunology / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D044404:Genomic Islands / Q000235:genetics / Q000276:immunology; D016480:Helicobacter pylori / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D039081:Integrin alpha5beta1 / Q000276:immunology / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000382:microbiology; D021962:Membrane Microdomains / Q000737:chemistry / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism; D010457:Peptidoglycan / Q000276:immunology / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D039081:Integrin alpha5beta1; D016209:Interleukin-8; D016328:NF-kappa B; C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; D010457:Peptidoglycan; C080866:cagA protein, Helicobacter pylori; D002784:Cholesterol