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• Helicobacter pylori outer membrane proteins and gastric inflammation
  Anar Dossumbekova
  Published on: 16 February 2006

• Published on: 16 February 2006

  Helicobacter pylori outer membrane proteins and gastric inflammation

  • Anar Dossumbekova, -
  • Other Contributors:
    • Christian Prinz, Lena Brenner, Markus Gerhard, Steffen Backert, Johannes G. Kusters, Roland M Schmid, Roland Rad

  Dear Editor,

  Approximately 4% of the H. pylori genome, significantly more than that of any other known bacterial species is composed of genes encoding outer membrane proteins (OMPs). The best described H. pylori OMP is the adhesin BabA, which is thought to mediate host/bacterial interactions and has been linked to microbial pathogenicity (1-4). The dissection of OMP function helps understanding the complex gastri...

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  Dear Editor,

  Approximately 4% of the H. pylori genome, significantly more than that of any other known bacterial species is composed of genes encoding outer membrane proteins (OMPs). The best described H. pylori OMP is the adhesin BabA, which is thought to mediate host/bacterial interactions and has been linked to microbial pathogenicity (1-4). The dissection of OMP function helps understanding the complex gastric biology of infection and may offer a possibility to identify persons with an increased risk for disease development.

  In an interesting and comprehensive study, Yoshio Yamaoka and co-workers analyzed expression of several outer membrane proteins (BabA, BabB, SabA, OipA) in a large number of H. pylori strains and described their association with gastroduodenal diseases (Yamaoka Y, Gut, Dec 1, 2005). One important finding was the strong linkage of OipA expression with the cag pathogenicity island (cagPAI), a major H. pylori virulence factor. The authors showed that in 94% of Columbian and U.S. H. pylori strains, CagA and OipA phenotypes are identical.

  OipA expression is regulated by slipped strand mispairing based on the number of CT dinucleotide repeats in the 5´ region of the gene. We sequenced this genetic region of H. pylori strains from 53 German patients with chronic gastritis and further determined the presence of the cagPAI marker gene cagA, as described previously (3;5). Similarly to Yamaoka and colleagues, we found linked expression of CagA and OipA in our European strain population, with 83% concordance (Figure 1A). The reason for this strong association is not understood. However, as there is no obvious common genetic mechanism controlling expression of the two genes, linkage of cagA and oipA seems to be based on selection in the host. Indeed, it has been demonstrated that H. pylori is capable to regulate OMP expression in vivo by phase variation as a mechanism of adaptation to changing environmental conditions (2). It is thus conceivable that OipA offers a selective advantage for cagPAI-positive bacteria that may for example prefer a gastric microenvironment in which OipA expression is beneficial.

  The influence of OipA on proinflammatory signalling has been discussed controversially (5-9). To investigate whether OipA is directly linked to pathogenesis, we performed mutagensis of the oipA and cagE genes for functional investigations in vitro. As shown in figure 1B, incubation of the cagA+/oipA+ strain B128 with KATO-III gastric epithelial cells leads to increased expression of IL-8, a signature chemokine of gastric inflammation. Whereas the isogenic oipA-knockout strain induces IL-8 expression to a similar extent, the cagE-deficient strain, which lacks a functional cagPAI, is severily impaired in its IL-8 inducing capacity. Despite using varying concentrations of bacteria (MOI 1-100), different cell lines and several independent oipA mutants of the H. pylori strains B128 and G27, we could not detect an influence of OipA on IL-8 expression/secretion (not shown). Similarly, we found no independent influence of OipA on gastric IL-8 expression and inflammation in vivo. As shown in figure 1C, IL-8 expression was higher in the mucosa of patients infected with cagA-positive strains than in patients infected with cagA- negative strains. However, in both groups chemokine expression was independent of the oipA status.

  Bacterial OMPs have multiple functions, e.g. as adhesins, porins, or play a role in complement resistance and immune regulation. Although several studies investigated the physiological role of OipA (5-9), its precise function is still not fully clear. The strong linkage with the cagPAI however, suggests that differential regulation of OipA expression by phase variation may contribute to the fitness of cagPAI-positive or - negative strains in vivo. This idea is supported by the finding that oipA- mutated cagPAI-positive H. pylori strains are impaired in their ability to colonize mongolian gerbils (9).

  Anar Dossumbekova*, Christian Prinz*, Markus Gerhard*, Lena Brenner*, Steffen Backert#, Johannes G Kusters&, Roland M Schmid*, Roland Rad*

  *2nd Department of Internal Medicine and Gastroenterology
  Technical University of Munich
  81675 Munich
  Germany

  #Institue of Medical Microbiology
  Otto-von-Guericke-Universität
  Magdeburg
  Germany

  &Department of Gastroenterology and Hepatology
  Erasmus MC-University Medical Centre
  Rotterdam
  The Netherlands

  References

  (1) Aspholm-Hurtig M, Dailide G, Lahmann M et al. Functional adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin. Science 2004;305(5683):519-22.

  (2) Solnick JV, Hansen LM, Salama NR et al. Modification of Helicobacter pylori outer membrane protein expression during experimental infection of rhesus macaques. Proc Natl Acad Sci U S A 2004;101(7):2106- 11.

  (3) Rad R, Gerhard M, Lang R et al. The Helicobacter pylori blood group antigen-binding adhesin facilitates bacterial colonization and augments a nonspecific immune response. J Immunol 2002;168(6):3033-41.

  (4) Prinz C, Schoniger M, Rad R et al. Key importance of the Helicobacter pylori adherence factor blood group antigen binding adhesin during chronic gastric inflammation. Cancer Res 2001;61(5):1903-9.

  (5) Yamaoka Y, Kwon DH, Graham DY. A M(r) 34,000 proinflammatory outer membrane protein (oipA) of Helicobacter pylori. Proc Natl Acad Sci U S A 2000;97(13):7533-8.

  (6) Ando T, Peek RM, Jr., Blaser MJ. Host cell responses to genotypically similar Helicobacter pylori isolates from United States and Japan. Clin Diagn Lab Immunol 2002;9(1):167-75.

  (7) Odenbreit S, Kavermann H, Puls J et al. CagA tyrosine phosphorylation and interleukin-8 induction by Helicobacter pylori are independent from alpAB, HopZ and bab group outer membrane proteins. Int J Med Microbiol 2002;292(3-4):257-66.

  (8) Yamaoka Y, Kikuchi S, el-Zimaity HM et al. Importance of Helicobacter pylori oipA in clinical presentation, gastric inflammation, and mucosal interleukin 8 production. Gastroenterology 2002;123(2):414-24.

  (9) Akanuma M, Maeda S, Ogura K et al. The evaluation of putative virulence factors of Helicobacter pylori for gastroduodenal disease by use of a short-term Mongolian gerbil infection model. J Infect Dis 2002;185(3):341-7.

  (10) de Jonge R, Durrani Z, Rijpkema SG et al. Role of the Helicobacter pylori outer-membrane proteins AlpA and AlpB in colonization of the guinea pig stomach. J Med Microbiol 2004;53(Pt 5):375-9.

  Figure 1: Influence of OipA and the cagPAI on IL-8 expression in vitro and in vivo. (A) Genetic characterization of H. pylori strains from 53 patients according to the cagA and oipA status. The cagA gene was detected by PCR as described previously (3). The oipA status was determined after sequencing of the 5´region of the gene. The "on" or "off" status depends on the number of CT dinucleotide repeats that render the gene in or out of frame. In 83% of strains, the cagA and oipA status identical. (B) IL-8 expression in gastric cancer cell line KATO-III after incubation with the H. pylori strain B128 and its isogenic oipA and cagE mutant strains at an MOI of 50. Bacterial mutagenesis was performed as described previously (10). Cytokine expression was analyzed by real-time RT-PCR and normalized to GAPDH expression, as described previously (3). Bars indicate the arithmetic mean and SEM from five samples per group. Shown is one out of 10 similar experiments. (C) IL-8 expression in the gastric mucosa of the 53 patients infected with the H. pylori strain types shown in (A). Statistically significant differences were found between any cagA- and cagA+ group (p<0,05, Student´s t-test). In contrast, there was no significant independent association of the oipA-on status with increased IL-8 expression.

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  Conflict of Interest:
  None declared.

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