"Targeted disruption of the epithelial-barrier by Helicobacter pylori"

Abstract

Helicobacter pylori colonizes the human gastric epithelium and induces chronic gastritis, which can lead to gastric cancer. Through cell-cell contacts the gastric epithelium forms a barrier to protect underlying tissue from pathogenic bacteria; however, H. pylori have evolved numerous strategies to perturb the integrity of the gastric barrier. In this review, we summarize recent research into the mechanisms through which H. pylori disrupts intercellular junctions and disrupts the gastric epithelial barrier.

Figure 1

Intercellular junctions form the epithelial barrier. Several bacteria, including H. pylori, and viruses interact with and disrupt cell-cell junctions of polarized epithelia. Intercellular junctions include tight junctions, adherens junctions, desmosomal junctions, and gap junctions.

Figure 2

Dysregulation of the tight junction by H. pylori. H. pylori preferentially bind in close proximity to the tight junction and disrupt gastric barrier function, cell adhesion, and cell polarity which culminates in an invasive phenotype. Tight junctions are composed of the integral membrane proteins occludin, claudins, and junctional adhesion molecule (JAM)-A, as well as zonula occludens-1 (ZO-1). Tight junction function is disrupted by urease activity and phosphorylation of myosin light chain (MLC) by myosin light chain kinase (MLCK) or Rho kinase (ROCK). Translocated CagA interacts with partitioning-defective 1 (PAR1) to inhibit phosphorylation by blocking PAR1 kinase activity and disrupts the tight junction. VacA also increases tight junction permeability.

Figure 3

Dysregulation of the adherens junction by H. pylori. H. pylori-translocated CagA interacts with E-cadherin and p120. This destabilizes the adherens junction and results in nuclear translocation of β-catenin and p120 and alterations in transcriptional activity. The H. pylori outer membrane protein OipA disrupts adherens junctions through redistribution of β-catenin, and H. pylori-secreted high-temperature requirement A (HtrA) cleaves E-cadherin, disrupting the adherens junction. Hypermethylation of the E-cadherin promoter also occurs in response to H. pylori infection and epithelial protein lost in neoplasm (EPLIN) binds α-catenin and links the cadherin-catenin complex with actin.