Introduction: Helicobacter pylori (Hp) colonizes the gastric mucus layer of around half of the world"s population. Although the infection is mostly asymptomatic, it is a major risk factor for gastritis, gastric and duodenal ulcers and gastric adenocarcinoma. Hp is recognized by epithelial cells and activates various signaling pathways through for instance pattern recognition receptors, resulting in inflammation. Hp can also induce DNA damage including double-strand breaks. The apoptosis system can be activated by infection, and pathogens have pro- or antiapoptotic effects. We have recently shown that various intracellular pathogens (bacteria and viruses) trigger sub-lethal signals in the mitochondrial apoptotic pathway.

Methods: We infected human gastric carcinoma cells (AGS) with Hp and tested for sub-lethal signals in the mitochondrial apoptosis pathway. We determined cytokine/chemokine release and DNA damage as a readout. We further investigated the release of mitochondrial cytochrome c and SMAC by Western Blot and confocal microscopy.

Results: Conditions could be established where infection with Hp did not induce cell death, but where sub-lethal signals in the mitochondrial apoptosis pathway could be identified. The pathway required the pattern recognition receptor NOD1 and specifically the BCL-2-family member BAK. We found that Hp-infection caused a pulse of release of the mitochondrial intermembrane-space protein SMAC apparently from the entire mitochondrial network into the cytosol. SMAC activated alternative NF-kB and was required for the normal secretion of chemokines upon infection. The activity of the mitochondrial apoptosis-pathway also caused DNA-ds-breaks, and in biopsies from Hp-patients we observed a correlation of evidence of sub-lethal signaling and the DNA-damage response.

Summary: The results identify sub-lethal signals in the mitochondrial apoptosis pathway during Hp-infection. With the release of mitochondrial proteins from the mitochondrial network, the results suggest a new model of mitochondrial signal. The evidence suggests that these signals contribute to inflammation and genome stress including mutations during chronic Hp-infection