Helicobacter pylori Counteracts the Apoptotic Action of Its VacA Toxin by Injecting the CagA Protein into Gastric Epithelial Cells

PLoS Pathogens

Patrice Boquet¹  Alexandra Canonici¹  Olivier Oregioni¹  Alessia Fabbri²  Vittorio Ricci³  Anna Sciullo³  Valentina Chiozzi³  Patrizia Sommi³  Amanda Oldani³  Veronique Hofman⁴  Mireille Cormont⁵ 

[1] Department of Clinical Bacteriology, Nice University Hospital, Nice, France;Department of Drug Research and Evaluation, Istituto Superiore di Sanità, Roma, Italy;Department of Physiology, Human Physiology Section, University of Pavia, Pavia, Italy;INSERM ERI-21, Faculty of Medicine, Nice, France;INSERM Unit 895 (Group 7), Faculty of Medicine, Nice, France

关键词: Apoptosis;    Mitochondria;    Helicobacter pylori;    Epithelial cells;    Phosphorylation;    Toxins;    Transfection;    Cytotoxins;   

DOI  :  10.1371/journal.ppat.1000603

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY