Functional analysis of the cag pathogenicity island in Helicobacter pylori isolates from patients with gastritis, peptic ulcer, and gastric cancer

被引:110
作者
Backert, S
Schwarz, T
Miehlke, S
Kirsch, C
Sommer, C
Kwok, T
Gerhard, M
Goebel, UB
Lehn, N
Koenig, W
Meyer, TF
机构
[1] Otto Von Guericke Univ, Dept Med Microbiol, D-39120 Magdeburg, Germany
[2] Humboldt Univ, Max Planck Inst Infect Biol, Dept Mol Biol, D-10117 Berlin, Germany
[3] Humboldt Univ, Inst Microbiol & Hyg, D-10117 Berlin, Germany
[4] Tech Univ Munich, Klinikum Rechts Isar, Dept Med 2, Lab Mol Gastroenterol, D-81675 Munich, Germany
[5] Tech Univ Hosp, Dept Med 1, D-01307 Dresden, Germany
[6] Univ Regensburg, Inst Med Microbiol, D-93053 Regensburg, Germany
关键词
D O I
10.1128/IAI.72.2.1043-1056.2004
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Helicobacter-pylori is the causative agent of a variety of gastric diseases, but the clinical relevance of bacterial virulence factors is still controversial. Virulent strains carrying the cag pathogenicity island (cagPAI) are thought to be key players in disease development. Here, we have compared cagPAI-dependent in vitro responses in H. pylori isolates obtained from 75 patients with gastritis, peptic ulcer, and gastric cancer (n = 25 in each group). AGS gastric epithelial cells were infected with each strain and assayed for (i) CagA expression, (ii) translocation and tyrosine phosphorylation of CagA, (iii) c-Src inactivation, (iv) cortactin dephosphorylation, (v) induction of actin cytoskeletal rearrangements associated with cell elongation, (vi) induction of cellular motility, and (vii) secretion of interleukin-8. Interestingly, we found high but similar prevalences of all of these cagPAI-dependent host cell responses (ranging from 56 to 80%) among the various groups of patients. This study revealed CagA proteins with unique features, CagA subspecies of various sizes, and new functional properties for the phenotypic outcomes. We further showed that induction of AGS cell motility and elongation are two independent processes. Our data corroborate epidemiological studies, which indicate a significant association of cagPAI presence and functionality with histopathological findings in gastritis, peptic ulcer, and gastric cancer patients, thus emphasizing the importance of the cagPAI for the pathogenicity of H. pylori. Nevertheless, we found no significant association of the specific H. pylori-induced responses with any particular patient group. This may indicate that the determination of disease development is highly complex and involves multiple bacterial and/or host factors.
引用
收藏
页码:1043 / 1056
页数:14
相关论文
共 81 条
[31]   The significance of cagA and vacA subtypes of Helicobacter pylori in the pathogenesis of inflammation and peptic ulceration [J].
Gunn, MC ;
Stephens, JC ;
Stewart, JAD ;
Rathbone, BJ ;
West, KP .
JOURNAL OF CLINICAL PATHOLOGY, 1998, 51 (10) :761-764
[32]  
Haas G, 2002, PROTEOMICS, V2, P313, DOI 10.1002/1615-9861(200203)2:3<313::AID-PROT313>3.0.CO
[33]  
2-7
[34]   SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein [J].
Higashi, H ;
Tsutsumi, R ;
Muto, S ;
Sugiyama, T ;
Azuma, T ;
Asaka, M ;
Hatakeyama, M .
SCIENCE, 2002, 295 (5555) :683-686
[35]   Helicobacter pylori CagA protein activates serum response element-driven transcription independently of tyrosine phosphorylation [J].
Hirata, Y ;
Maeda, S ;
Mitsuno, Y ;
Tateishi, K ;
Yanai, A ;
Akanuma, M ;
Yoshida, H ;
Kawabe, T ;
Shiratori, Y ;
Omata, M .
GASTROENTEROLOGY, 2002, 123 (06) :1962-1971
[36]   A TAIL OF 2 SRCS - MUTATIS MUTANDIS [J].
HUNTER, T .
CELL, 1987, 49 (01) :1-4
[37]   Helicobacter pylori strain-specific differences in genetic content, identified by microarray, influence host inflammatory responses [J].
Israel, DA ;
Salama, N ;
Arnold, CN ;
Moss, SF ;
Ando, T ;
Wirth, HP ;
Tham, KT ;
Camorlinga, M ;
Blaser, MJ ;
Falkow, S ;
Peek, RM .
JOURNAL OF CLINICAL INVESTIGATION, 2001, 107 (05) :611-620
[38]  
Jones NL, 1997, AM J PATHOL, V151, P1695
[39]   Helicobacter pylori water extract induces interleukin-8 production by gastric epithelial cells [J].
Kassai, K ;
Yoshikawa, T ;
Yoshida, N ;
Hashiramoto, A ;
Kondo, M ;
Murase, H .
DIGESTIVE DISEASES AND SCIENCES, 1999, 44 (02) :237-242
[40]   cag plus Helicobacter pylori induce transactivation of the epidermal growth factor receptor in AGS gastric epithelial cells [J].
Keates, S ;
Sougioultzis, S ;
Keates, AC ;
Zhao, DZ ;
Peek, RM ;
Shaw, LM ;
Kelly, CP .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (51) :48127-48134