Polyamine- and NADPH-dependent generation of ROS during Helicobacter pylori infection: A blessing in disguise

Abstract

Helicobacter pylori is a Gram-negative bacterium that specifically colonizes the gastric ecological niche. During the infectious process, which results in diseases ranging from chronic gastritis to gastric cancer, the host response is characterized by the activation of the innate immunity of gastric epithelial cells and macrophages. These cells thus produce effector molecules such as reactive oxygen species (ROS) to counteract the infection. The generation of ROS in response to H. pylori involves two canonical pathways: 1) the NADPH-dependent reduction of molecular oxygen to generate O₂^•-, which can dismute to generate ROS; and 2) the back-conversion of the polyamine spermine into spermidine through the enzyme spermine oxidase, leading to H₂O₂ production. Although these products have the potential to affect the survival of bacteria, H. pylori has acquired numerous strategies to counteract their deleterious effects. Nonetheless, ROS-mediated oxidative DNA damage and mutations may participate in the adaptation of H. pylori to its ecological niche. Lastly, ROS have been shown to play a major role in the development of the inflammation and carcinogenesis. It is the purpose of this review to summarize the literature about the production of ROS during H. pylori infection and their role in this infectious gastric disease.

Keywords: Gastric cancer; Helicobacter pylori; NADPH oxidase; Polyamines; Reactive oxygen species.

Fig. 1

H. pylori-infected macrophages produces H₂O₂ from L-arginine. H. pylori induces SLC7A2 expression allowing the uptake of L-arginine in macrophages. The induction of ARG2, ODC, which requires a MYC-dependent pathway, and SMOX leads to the release of H₂O₂.

Fig. 2

Regulation of NOX by H. pylori. NOX1 is induced in gastric epithelial cells through a PI3K/RAC1 signaling pathway; in these cells, the production of O₂^•− stimulate the expression of APEX that blocks RAC1. In myeloid cells, the expression of NOX2 requires a NapA/PI3K signals. DUOX2 has been shown to be induced in the gastric tissue of infected animals, but the subcellular localization of this enzyme remains unknown. PHD, peroxidase homology domain.

Fig. 3

Biochemical pathways used by H. pylori to counteract ROS. The enzyme KatA is transported to the periplasm by the action of KapA and the Tat system. O₂^•− is converted into H₂O by SodB and KatA. Hydroperoxides, peroxynitrites, and H₂O₂ are reduced by the Prx/TrxA system. NapA protects H. pylori from DNA oxidation by an unknown mechanism. NpH and MutS are involved in oxidative DNA repair.