title: In depth analysis of the Helicobacter pylori cag pathogenicity island transcriptional responses.
abstract: The severity of symptoms elicited by the widespread human pathogen Helicobacter pylori is strongly influenced by the genetic diversity of the infecting strain. Among the most important pathogen factors that carry an increased risk for gastric cancer are specific genotypes of the cag pathogenicity island (cag-PAI), encoding a type IV secretion system (T4SS) responsible for the translocation of the CagA effector oncoprotein. To date, little is known about the regulatory events important for the expression of a functional cag-T4SS. Here we demonstrate that the cag-PAI cistrons are subjected to a complex network of direct and indirect transcriptional regulations. We show that promoters of cag operons encoding structural T4SS components display homogeneous transcript levels, while promoters of cag operons encoding accessory factors vary considerably in their basal transcription levels and responses. Most cag promoters are transcriptionally responsive to growth-phase, pH and other stress-factors, although in many cases in a pleiotropic fashion. Interestingly, transcription from the Pcagζ promoter controlling the expression of transglycolase and T4SS stabilizing factors, is triggered by co-culture with a gastric cell line, providing an explanation for the increased formation of the secretion system observed upon bacterial contact with host cells. Finally, we demonstrate that the highly transcribed cagA oncogene is repressed by iron limitation through a direct apo-Fur regulation mechanism. Together the results shed light on regulatory aspects of the cag-PAI, which may be involved in relevant molecular and etiological aspects of H. pylori pathogenesis.
authors.affiliation: Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vannini
authors.affiliation: Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Roncarati
authors.affiliation: Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Spinsanti
authors.affiliation: Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Scarlato
authors.affiliation: Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Danielli
mesh_terms: D000942:Antigens, Bacterial / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism; D001483:Base Sequence; D045744:Cell Line, Tumor; D004777:Environment; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D017930:Genes, Reporter; D044404:Genomic Islands / Q000235:genetics*; D016480:Helicobacter pylori / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007501:Iron / Q000494:pharmacology; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C080866:cagA protein, Helicobacter pylori; D007501:Iron