The Immune Battle against Helicobacter pylori Infection: NO Offense

Abstract

Helicobacter pylori is a successful pathogen of the human stomach. Despite a vigorous immune response by the gastric mucosa, the bacterium survives in its ecological niche, thus favoring diseases ranging from chronic gastritis to adenocarcinoma. The current literature demonstrates that high-output of nitric oxide (NO) production by the inducible enzyme NO synthase-2 (NOS2) plays major functions in host defense against bacterial infections. However, pathogens have elaborated several strategies to counteract the deleterious effects of NO; this includes inhibition of host NO synthesis and transcriptional regulation in response to reactive nitrogen species, allowing the bacteria to face the nitrosative stress. Moreover, NO is also a critical mediator of inflammation and carcinogenesis. In this context, we review the recent findings on the expression of NOS2 in H. pylori-infected gastric tissues and epithelial cells, the role of NO in H. pylori-related diseases and H. pylori gene expression, and the mechanisms whereby H. pylori regulates NO synthesis by host cells.

Keywords: Helicobacter pylori; gastric cancer; nitric oxide; polyamines.

Figure 1

Key Figure: H. pylori Infection in an NO World. H. pylori stimulates gastric epithelial cells and thus induces an innate response characterized by the production of chemokines, which leads to the recruitment of myeloid cells, including macrophages, in the gastric mucosa (1a). H. pylori-derived factors, such as urease, or the bacterium itself stimulate NOS2 expression in macrophages and in gastric epithelial cells (1b). NO releases by these activated cells has a cytotoxic effect on H. pylori and provokes the formation of 8-nitroguanine (8-NO2-Gua; 1c). The cellular changes induced by the oncoprotein CagA and the mutagenesis reinforced by the activity of 8-NO2-Gua may contribute to the development of gastric cancer. Ultimately, H. pylori regulates NO production by numerous strategies (1d).

Figure 2

RNI Detoxification in H. pylori. High-output NOS2-dependent NO production by macrophages is released outside the cells and may affect the bacteria at distance from producing cells or is converted in GSNO to target phagocytized H. pylori. RNI inhibit H. pylori respiration and the activity of the arginase RocF, thus decreasing the synthesis of the urease substrate, urea. H. pylori counteracts the deleterious effect of RNI using the NO reductase NorH, the GSNO reductase FrxA, the thioredoxin TrxA that also serves as a chaperone for RocF, and the CrdSR-dependent upregulation of FecA and FrpB that are involved in iron transport. ONOO⁻ detoxification occurs through the urease-dependent production of CO₂ and the peroxiredoxin AhpC.

Figure 3

Regulation of Macrophage NO Production by H. pylori. The infection of murine macrophages by H. pylori results in the expression of Slc7a2, Odc, Arg2, Hmox-1 (the gene encoding HO-1), and Nos2 mRNA. L-arginine uptake is supported by SLC7A2, promotes NOS2 translation, and is required for NO production. ARG2 and H. pylori arginase RocF deplete intracellular and extracellular L-arginine, respectively, thus decreasing the synthesis of NOS2 and generation of NO. Spermine (Spm), which is synthesized through the ARG2-ODC pathway, inhibits SLC7A2-dependent L-arginine uptake and thus NOS2 translation and activity. Asymmetric dimethylarginine (ADMA) is generated during H. pylori infection and is a natural NOS2 inhibitor. Abbreviations: Put, Putrescine; Spd, Spermidine.