Abstract
Infection with Helicobacter pylori is responsible for gastritis and gastroduodenal ulcers but is also a high risk factor for the development of gastric adenocarcinoma and lymphoma. The most pathogenic H. pylori strains (i.e., the so-called type I strains) associate the CagA virulence protein with an active VacA cytotoxin but the rationale for this association is unknown. CagA, directly injected by the bacterium into colonized epithelium via a type IV secretion system, leads to cellular morphological, anti-apoptotic and proinflammatory effects responsible in the long-term (years or decades) for ulcer and cancer. VacA, via pinocytosis and intracellular trafficking, induces epithelial cell apoptosis and vacuolation. Using human gastric epithelial cells in culture transfected with cDNA encoding for either the wild-type 38 kDa C-terminal signaling domain of CagA or its non-tyrosine-phosphorylatable mutant form, we found that, depending on tyrosine-phosphorylation by host kinases, CagA inhibited VacA-induced apoptosis by two complementary mechanisms. Tyrosine-phosphorylated CagA prevented pinocytosed VacA to reach its target intracellular compartments. Unphosphorylated CagA triggered an anti-apoptotic activity blocking VacA-induced apoptosis at the mitochondrial level without affecting the intracellular trafficking of the toxin. Assaying the level of apoptosis of gastric epithelial cells infected with wild-type CagA+/VacA+ H. pylori or isogenic mutants lacking of either CagA or VacA, we confirmed the results obtained in cells transfected with the CagA C-ter constructions showing that CagA antagonizes VacA-induced apoptosis. VacA toxin plays a role during H. pylori stomach colonization. However, once bacteria have colonized the gastric niche, the apoptotic action of VacA might be detrimental for the survival of H. pylori adherent to the mucosa. CagA association with VacA is thus a novel, highly ingenious microbial strategy to locally protect its ecological niche against a bacterial virulence factor, with however detrimental consequences for the human host.
Highlights
Infection with Helicobacter pylori is responsible for gastritis and gastroduodenal ulcers but is a high risk factor for the development of mucosa-associated lymphoid-like tissue (MALT) lymphoma as well as gastric adenocarcinoma [1]
We show that the H. pylori cytotoxin-associated gene A (CagA) protein counteracts, by two distinct non-overlapping mechanisms, the apoptotic activity of the H. pylori VacA toxin on human gastric epithelial cells so as to allow a protection of the bacterium niche against VacA, giving a rationale for the association of these two virulence factors in the most pathogenic H. pylori strains
While exerting a beneficial role for survival and growth of the bacterium by counteracting VacA toxin, CagA injection in the gastric epithelial cells triggers proinflammatory and anti-apoptotic responses which are detrimental for the human host in the long-term and favor the development of ulcer and cancer
Summary
Infection with Helicobacter pylori is responsible for gastritis and gastroduodenal ulcers but is a high risk factor for the development of mucosa-associated lymphoid-like tissue (MALT) lymphoma as well as gastric adenocarcinoma [1]. H. pylori strains have been classified by the presence or the absence of two virulence factors, namely: an active vacuolating toxin VacA [2] and a 40-kbp pathogenicity island (cag PAI) encoding the 120– 145 kDa immunodominant protein termed cytotoxin-associated gene A (CagA) as well as a type IV secretion system (TFSS) that injects CagA into the host cell [3]. The CagA protein is probably the pivotal bacterial determinant for the development of a severe gastric inflammation that favors, in the long-term (years or decades), the occurrence of ulcer and cancer [5]. As suggested [11], VacA may play a role in the early steps of bacterial gastric colonization
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