- Helicobacter pylori colonizes the gastric epithelium by strategically adhering near the apical-junctional complex, a region rich in tight and adherens junction proteins that maintain epithelial integrity. This precise localization is achieved through a coordinated interplay of outer membrane adhesins and injected virulence factors that exploit host cell architecture to establish a persistent infection. The initial step involves bacterial adhesion, which is primarily mediated by a family of surface-exposed proteins.
- Two major adhesins, BabA and SabA, play critical roles in initial attachment. BabA binds to fucosylated Lewis b (Leᵇ) antigens expressed on the gastric mucosa, while SabA targets sialyl-Lewis x (sLeˣ) glycans that are upregulated during inflammation. These interactions localize H. pylori to regions near epithelial cell-cell junctions, creating an optimal environment for effector translocation and manipulation of host cell function. Additional adhesins such as AlpA/B and HopZ contribute to stable colonization by binding to extracellular matrix proteins like laminin or undefined epithelial receptors, although their precise molecular targets within the junctional complex remain less well characterized.
- Following adhesion, H. pylori utilizes its type IV secretion system (T4SS) to translocate the effector protein CagA directly into host epithelial cells. Once inside the cell, unphosphorylated CagA interacts with junctional proteins such as ZO-1 and JAM-A. These interactions lead to the relocalization of these proteins away from their native positions at the tight junctions to the sites of bacterial attachment, forming abnormal, ectopic tight junction-like complexes. This mislocalization compromises the structural and functional integrity of the tight junction barrier.
- As a result of these disruptions, the epithelial barrier becomes leaky, allowing the passage of solutes and potentially harmful substances. This has been demonstrated using permeability assays, such as those involving albumin-biotin leakage, which show increased paracellular permeability in cells infected with H. pylori. Importantly, the pore-forming toxin VacA works in synergy with CagA to exacerbate this barrier dysfunction, further weakening epithelial defense mechanisms and promoting chronic infection.
- In addition to dismantling tight junctions, CagA interferes with the apical-basal polarity of epithelial cells by targeting the polarity-regulating kinase PAR1b/MARK2. By binding and inhibiting PAR1b’s kinase activity, CagA causes a loss of epithelial polarity, disrupting cellular orientation and organization. This facilitates H. pylori’s access to basolateral surfaces and intercellular spaces, enabling deeper colonization and immune evasion.
- Moreover, CagA targets the adherens junction, particularly the E-cadherin/β-catenin complex. CagA-mediated destabilization of this complex leads to a breakdown in cell-cell adhesion. This not only compromises epithelial cohesion but also releases β-catenin into the cytoplasm, where it may translocate to the nucleus and activate Wnt/β-catenin signaling pathways, which are implicated in cell proliferation and early stages of carcinogenesis.
- The consequences of these molecular events are profound. Chronic exposure to CagA induces dysplastic epithelial morphology, including irregular cell shapes, multilayering, and loss of monolayer organization—hallmarks of precancerous transformation. By undermining junctional stability and polarity, H. pylori crafts a microenvironment that supports bacterial persistence, shields the bacteria from immune clearance, and sets the stage for long-term inflammation and potentially malignant transformation.
- In summary, H. pylori exploits its adhesins to anchor near the apical-junctional complex and subsequently uses CagA to hijack junctional and polarity proteins, including ZO-1, JAM-A, PAR1b, and E-cadherin. This multifaceted strategy weakens the epithelial barrier, disrupts cell polarity, and facilitates persistent colonization—contributing to gastric disease progression and oncogenic risk.
