Helicobacter pylori and CagA under conditions of iron deficiency

Abstract

Iron deficiency is the most common nutritional deficiency worldwide and compelling evidence has demonstrated that this condition heightens the risk of gastric cancer. Infection with Helicobacter pylori is the strongest known risk factor for the development of gastric adenocarcinoma. Recent work has demonstrated that, under conditions of iron deficiency, H. pylori-induced gastric carcinogenesis is augmented through increased formation of the strain-specific cag type IV secretion system and enhanced delivery of the bacterial oncoprotein CagA into host cells. Although CagA is a potent virulence factor that promotes oncogenic responses, additional studies have now demonstrated that CagA modulates host cell iron homeostasis in vitro and fundamental metabolic functions of the bacterial cell in vivo. Here we discuss these findings and describe working models by which CagA exerts its effects on gastric epithelial cells, with particular emphasis on its potential role in modulation of host iron homeostasis.

Keywords: CagA; Helicobacter pylori; cag type IV secretion system, gastric cancer; iron deficiency.

Figure 1.

The H. pylori cag type IV secretion system. The cag pathogenicity island encodes a bacterial type IV secretion system, which facilitates the delivery of CagA into gastric epithelial cells. Once inside the cell, CagA can undergo tyrosine phosphorylation by Src and Abl family kinases, where it then interacts with SHP2 and mediates ERK1/2 signaling and ultimately induces morphologic changes. CagA can also remain unphosphorylated, where it interacts with components of both the tight junctions (TJ) and adherens junctions (AJ), leading to dissociation of junctional complexes. In particular, unphosphorylated CagA can lead to disruption of β-catenin (β) from the adherens junction, leading to β-catenin-dependent transcriptional activation of mitogenic responses. CagA can also lead to activation of NF-κB, which leads to NF-κB-mediated proinflammatory responses, such as the induction of IL-8.

Figure 2.

Enhanced formation and function of the cag type IV secretion system under conditions of iron depletion and its role in disruption of host cell iron homeostasis. H. pylori leads to proinflammatory responses, such as the induction of IL-8, and this response is mediated by translocation of CagA into gastric epithelial cells. Recent evidence has demonstrated that H. pylori can facilitate the mislocalization of the transferrin receptor from the basolateral surface to the apical surface in a CagA-dependent manner. Under conditions of iron deficiency, the formation and function of the cag type IV secretion system is augmented, leading to increased CagA translocation into gastric epithelial cells and increased proinflammatory responses, such as IL-8, and potentially increased access to host iron supplies through enhanced disruption and mislocalization of the transferrin receptor.

Figure 3.

CagA is required for spiral morphology under conditions of iron deficiency in vivo. Mongolian gerbils were maintained on iron-normal or iron-deficient diets and then challenged with H. pylori cagA⁻ isogenic mutants. Gastric tissues were fixed in paraformaldehyde phosphate buffer fixative and processed, as previously described. Under normal iron conditions, H. pylori cagA^- isogenic mutants exhibited wild-type spiral colony morphology that was characterized by the classical helical shape. However, under conditions of iron deficiency, H. pylori cagA^- isogenic mutants exhibited altered bacterial shape, characterized by a transition to a coccoid morphology, suggesting that CagA is required for spiral morphology in vivo.