Molecular mechanisms of epithelial-barrier disruption by Helicobacter pylori

doi:10.1016/j.tim.2008.05.005

Trends in Microbiology

Volume 16, Issue 8, August 2008, Pages 397-405

https://doi.org/10.1016/j.tim.2008.05.005 Get rights and content

Intact intercellular junctions and cell-matrix contacts are important structures in the formation and maintenance of epithelial-barrier functions against microbes. The human gastric pathogen Helicobacter pylori developed a remarkable network of strategies to alter these epithelial cell–cell and cell–matrix adhesions, which are implicated in inflammation, proliferation, cell migration and invasive growth. This review focuses on recent findings on H. pylori-induced host-cell signaling. We propose a stepwise model for how H. pylori interacts with components of focal adhesions and intercellular tight and adherens junctions to disrupt the epithelial layer, providing novel insights into the pathogenesis of H. pylori.

Section snippets

The human mucosa: first barrier against microbial infections

The gastric mucosal epithelium is an important inner cell layer that not only controls digestive, absorptive and secretory functions but also forms the first barrier against pathogenic microorganisms. The human pathogen Helicobacter pylori colonizes the gastric epithelium as a unique niche in the stomach. Highly virulent strains harbor the cag pathogenicity island (cagPAI), which encodes a type-IV secretion system (T4SS) to inject the bacterial cytotoxin-associated gene A (CagA) oncoprotein (

Cellular aspects of H. pylori CagA-induced epithelial de-differentiation

Numerous studies have shown that colonization of gastric epithelial cells with H. pylori in vitro induces a drastic cell migration and changes in cell morphology, cell–cell and cell–matrix adhesion that might influence the physiological balance and integrity of the epithelium in vivo10, 11. In addition to CagA, the vacuolating cytotoxin VacA has also been identified as another important virulence factor of H. pylori. VacA is constitutively secreted by the bacteria and binds to its receptors,

Depolarization of epithelial cells involves alterations of TJs

TJs are important structures in the intercellular adhesion of polarized epithelial cells, and they prevent the leakage of molecules across the epithelia and diffusion of integral proteins and lipids (Box 2). They are composed of multiple proteins such as the junctional adhesion molecule (JAM)-1, occludin, claudin, zonula occludens (ZO)-1 and others. TJs are regulated by a signaling complex including atypical protein kinase C (aPKC), which phosphorylates partitioning-defective (Par) proteins (

Disruption of AJs by H. pylori

AJs are formed by a complex of membrane proteins and associated factors, including the key molecules E-cadherin and α- and β-catenins (Figure 1c). AJs not only function in cell-to-cell adhesion but also have important roles in gastric carcinogenesis. In the late stages of all carcinoma types, downregulation of E-cadherin occurs frequently and is closely correlated with invasive growth and metastasis (Box 2). E-cadherin function can be inactivated by (i) reduced E-cadherin expression, (ii)

Disruption of AJs by ectopically expressed CagA

Transfected CagA can physically interact with E-cadherin to impair the interaction between E-cadherin and β-catenin and, hence, the stability of the AJ complex [8]. This might be of particular importance because the stability of AJs is crucial in the function of E-cadherin as a tumor suppressor. Catenins are usually sequestered by cadherins in the cadherin–catenin complex (Figure 1c). Once β-catenin is released it is phosphorylated by glycogen synthase kinase 3β (GSK-3β) in the adenomatous

Disruption of AJs by H. pylori: more than CagA?

Signaling in epithelial cells infected with H. pylori seems to be highly sophisticated. The influence of CagA on AJs was further supported by the finding that translocated CagA^PY can also interact with CT10 regulator of kinase (Crk) adaptor proteins. The CagA^PY–Crk complex stimulates the breakdown of AJs, which leads to the loss of cell adhesion and to the induction of proliferation [7]. Although not investigated yet, the CagA^PY–Crk complex might form a ternary complex with E-cadherin because

FAs: importance for CagA injection and cell elongation

Migration of healthy, polarized epithelial cells requires a coordinated assembly and disassembly of FAs to move the cell body on the ECM and actin polymerization along the plasma membrane to contract the cell cortex (Box 2 and Figure 1d). In normal cells, these dynamic actin rearrangements are crucially controlled by focal adhesion kinase (FAK), Src and the small GTPase RhoA and its effector proteins to generate cortical tension and to maintain round cell morphology; the small GTPases Rac and

Multi-step model for H. pylori-induced epithelial-barrier disruption

Early studies indicated that CagA is a major player in targeting cell-to-cell junctions 6, 11, 5, 8, but how can this be achieved when the β₁-integrin receptor for injection of CagA is on the basal membrane and not accessible to the bacteria in intact tissues? How does H. pylori disrupt the epithelial barrier? In light of the previously described studies, we propose that multiple bacterial factors and host processes are involved in this scenario (Figure 2a). We propose that pathogenicity island

Concluding remarks and future perspectives

We are just beginning to understand the impact of H. pylori on cell-to-cell junctions and FAs. However, it is becoming obvious that H. pylori, like other pathogens, combines several strategies to alter cell adhesion, implying multi-step processes in the loss of cell polarity. In fact, CagA is a potent and multifunctional signaling molecule, and further studies are necessary to obtain a deeper understanding of the CagA-signaling network. Although CagA is crucial in intracellular signal

Acknowledgements

We apologize to all colleagues whose important works could not be cited here owing to space restrictions. We thank Vittorio Ricci (University of Padua) for providing us with the electron microscopy image in Figure 2b. The work of S.B. is supported by the Priority Program SPP1150 of the Deutsche Forschungsgemeinschaft (Ba1671/3–3) and CampEc-NET (EU SafeFoodera program). S.W. is supported by the Jürgen-Manchot-Stiftung and the Deutsche Forschungsgemeinschaft (We2843/2–1).

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Citation Excerpt :
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Trends in Microbiology

ReviewMolecular mechanisms of epithelial-barrier disruption by Helicobacter pylori

Section snippets

The human mucosa: first barrier against microbial infections

Cellular aspects of H. pylori CagA-induced epithelial de-differentiation

Depolarization of epithelial cells involves alterations of TJs

Disruption of AJs by H. pylori

Disruption of AJs by ectopically expressed CagA

Disruption of AJs by H. pylori: more than CagA?

FAs: importance for CagA injection and cell elongation

Multi-step model for H. pylori-induced epithelial-barrier disruption

Concluding remarks and future perspectives

Acknowledgements

Curr. Opin. Microbiol.

Curr. Opin. Microbiol.

Curr. Opin. Microbiol.

J. Biol. Chem.

Gastroenterology

Trends Biochem. Sci.

Microbes Infect.

Trends Microbiol.

Pathol. Res. Pract.

Trends Cardiovasc. Med.

J. Biol. Chem.

Exp. Cell Res.

Cell

Trends Cell Biol.

Curr. Opin. Cell Biol.

J. Biol. Chem.

J. Biol. Chem.

Gastroenterology

Cell Host Microbe

Mol. Cell

J. Biol. Chem.

Helicobacter infection and gastric neoplasia

J. Pathol.

Helicobacter pylori persistence: biology and disease

J. Clin. Invest.

The biological model of gastric carcinogenesis

IARC Sci. Publ.157

Cellular and molecular aspects of gastric cancer

World J. Gastroenterol.

Deregulation of β-catenin signal by Helicobacter pylori CagA requires the CagA-multimerization sequence

Int. J. Cancer

Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA

Science

Interaction of CagA with Crk plays an important role in Helicobacter pylori-induced loss of gastric epithelial cell adhesion

J. Exp. Med.

Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells

Oncogene

Helicobacter exploits integrin for type IV secretion and kinase activation

Nature

A Mr 34 000 proinflammatory outer membrane protein (oipA) of Helicobacter pylori

Proc. Natl. Acad. Sci. U. S. A.

Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island

Nat. Immunol.

Phosphorylation of Helicobacter pylori CagA by c-Abl leads to cell motility

Oncogene

c-Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs

Mol. Microbiol.

Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse

Proc. Natl. Acad. Sci. U. S. A.

Parsing the polarity code

Nat. Rev. Mol. Cell Biol.

Loss of the tight junction protein claudin 4 correlates with histological growth-pattern and differentiation in advanced gastric adenocarcinoma

Oncol. Rep.

Review
Molecular mechanisms of epithelial-barrier disruption by Helicobacter pylori

A M_r 34 000 proinflammatory outer membrane protein (oipA) of Helicobacter pylori