Toxic and inflammatory activities of virulence
factors of Helicobacter pylori
Cesare MONTECUCCO
Helicobacter pylori (Hp) chronically
infects the stomach of the majority of the human population; in a minority
of patients, Hp is associated with severe gastroduodenal diseases, including
active chronic gastritis, peptic ulcers and stomach cancers. Hp resides within
and below the mucus layer which protects the stomach epithelial lyning. This
ecological niche is characterized by a paucity of nutrients. Here, I will
discuss the mechanism of action of two main virulence factors of H. pylori
which alter the stomach mucosa to induce release of nutrients necessary to
bacterial growth.
The vacuolating
cytotoxin VacA induces vacuolization of late endosomal compartments with mis-targeting
of acid hydrolases and degradation of the mucus layer, which becomes more
permeable to nutrients from the stomach lumen. VacA makes transmembrane anion
selective channels, which increase the lumenal osmotic pressure thereby causing
swelling of late endosomes. In addition, VacA causes a selective increase
in the paracellular route of permeability of polarized epithelial monolayers
to small molecules, permitting the passage of nutrients from the basolateral
side to the apically located bacteria thus supporting their growth.
The neutrophil
activating protein HP-NAP was found to activate mast-cells, neutrophils and
monocytes via a pertussis toxin sensitive G protein-coupled receptor. A limited
tissue inflammation makes additional nutrients available to the bacterium.
At the same time, oxygen radicals can generate mutagenic substances which
could contribute to the increased risk of developing cancer. In addition both
VacA and HP-NAP are strong activators of Mast cells and the complex of these
pro-inflammatory activities is suggested to be functional to to the growth
of the bacterium because a low state of local tissue inflammation is not
perceived by the host while, at the same time, bacterial nutrients are made
available.