title: CagY Is an Immune-Sensitive Regulator of the Helicobacter pylori Type IV Secretion System.
abstract: Peptic ulcer disease and gastric cancer are caused most often by Helicobacter pylori strains that harbor the cag pathogenicity island, which encodes a type IV secretion system (T4SS) that injects the CagA oncoprotein into host cells. cagY is an essential gene in the T4SS and has an unusual DNA repeat structure that predicts in-frame insertions and deletions. These cagY recombination events typically lead to a reduction in T4SS function in mouse and primate models. We examined the role of the immune response in cagY-dependent modulation of T4SS function.
  
  
  
  H pylori T4SS function was assessed by measuring CagA translocation and the capacity to induce interleukin (IL)8 in gastric epithelial cells. cagY recombination was determined by changes in polymerase chain reaction restriction fragment-length polymorphisms. T4SS function and cagY in H pylori from C57BL/6 mice were compared with strains recovered from Rag1-/- mice, T- and B-cell-deficient mice, mice with deletion of the interferon gamma receptor (IFNGR) or IL10, and Rag1-/- mice that received adoptive transfer of control or Ifng-/- CD4+ T cells. To assess relevance to human beings, T4SS function and cagY recombination were assessed in strains obtained sequentially from a patient after 7.4 years of infection.
  
  
  
  H pylori infection of T-cell-deficient and Ifngr1-/- mice, and transfer of CD4+ T cells to Rag1-/- mice, showed that cagY-mediated loss of T4SS function requires a T-helper 1-mediated immune response. Loss of T4SS function and cagY recombination were more pronounced in Il10-/- mice, and in control mice infected with H pylori that expressed a more inflammatory form of cagY. Complementation analysis of H pylori strains isolated from a patient over time showed changes in T4SS function that were dependent on recombination in cagY.
  
  
  
  Analysis of H pylori strains from mice and from a chronically infected patient showed that CagY functions as an immune-sensitive regulator of T4SS function. We propose that this is a bacterial adaptation to maximize persistent infection and transmission to a new host under conditions of a robust inflammatory response.
authors: Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California.
authors: Roberto M
authors: RM
authors: Barrozo
authors: Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California.
authors: Lori M
authors: LM
authors: Hansen
authors: Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California.
authors: Anna M
authors: AM
authors: Lam
authors: Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California.
authors: Emma C
authors: EC
authors: Skoog
authors: Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California.
authors: Miriam E
authors: ME
authors: Martin
authors: Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California.
authors: Lucy P
authors: LP
authors: Cai
authors: Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California.
authors: Yong
authors: Y
authors: Lin
authors: Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.
authors: Andreas
authors: A
authors: Latoscha
authors: Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany; Deutsches Zentrum für Infektionsforschung, German Center for Infection Research, Hannover-Braunschweig Partner Site, Hannover, Germany.
authors: Sebastian
authors: S
authors: Suerbaum
authors: California National Primate Research Center, University of California, Davis School of Medicine, Davis, California.
authors: Don R
authors: DR
authors: Canfield
authors: Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California; California National Primate Research Center, University of California, Davis School of Medicine, Davis, California; Department of Medicine, University of California, Davis School of Medicine, Davis, California; Department of Microbiology and Immunology, University of California, Davis School of Medicine, Davis, California. Electronic address: jvsolnick@ucdavis.edu.
authors: Jay V
authors: JV
authors: Solnick
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics; D001426:Bacterial Proteins / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D002908:Chronic Disease; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D005753:Gastric Mucosa / Q000166:cytology; D005756:Gastritis / Q000276:immunology / Q000382:microbiology; D016481:Helicobacter Infections / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D016480:Helicobacter pylori / Q000235:genetics* / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D011995:Recombination, Genetic; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer; D013997:Time Factors; D014178:Translocation, Genetic; D000069319:Type IV Secretion Systems / Q000235:genetics*; D000096743:Interferon gamma Receptor
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D018398:Homeodomain Proteins; D007371:Interferon-gamma; D016753:Interleukin-10; D016209:Interleukin-8; D017471:Receptors, Interferon; D000069319:Type IV Secretion Systems; D000096743:Interferon gamma Receptor; C080866:cagA protein, Helicobacter pylori; C064658:RAG-1 protein
keywords: Adaptation; Bacteria; IL8; Stomach