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5th International congress on Infectious Diseases

Berlin, Germany

Eliette Touati

Institut Pasteur
France

Title: Consequences of H. pylori infection and its VacA cytotoxin on mitochondria and mitochondrial DNA: Impact on gastric pathogenesis

Biography

Biography: Eliette Touati

Abstract

Statement of the Problem: Mitochondria alterations and mitochondrial DNA (mtDNA) instabilities are a hallmark of cancer. Mitochondria represent strategic targets for pathogens also including Helicobacter pylori. This bacterium is a major risk factor  for gastric cancer. Up to now, the cytotoxin VacA is the only one H. pylori factor known to target and damage mitochondria.

Methodology & Theoretical Orientation: By in vitro infection of gastric epithelial cells with wild-type and VacA-deficient H. pylori strains, treatment of cells with purified VacA proteins and infection of a mouse model, we show that H. pylori deregulates mitochondria by two novel mechanisms, both rather associated with host cell survival. First, early upon infection VacA induces transient increase of mitochondrial translocases and a dramatic accumulation of the mitochondrial DNA replication and maintenance factors POLG and TFAM. These events occur when VacA is not detected intracellularly, therefore do not require the direct interaction of the cytotoxin with the organelle. They occur independently of the VacA vacuolating activity. In vivo, these alterations coincide with the evolution of gastric lesions towards severity, concomitantly with the induction of mtDNA mutations and depletion of mtDNA content. Second, H. pylorus also induces VacA-independent alteration of mitochondrial replication and import components, suggesting the involvement of additional H. pylori activities in mitochondria-mediated effects.

Conclusions & Significance: Our findings reveal a novel and early inducer effect of H. pylori infection on mitochondrial translocases and the mtDNA replication/transcription machinery components POLG and TFAM. Moreover, we show that VacA does not account for all consequences of H. pylori infection at mitochondria, pointing to the involvement of other bacterial activities, yet to be determined. These effects of H. pylori infection are also relevant in vivo, suggesting that mitochondrial alterations impact H. pylori-induced gastric inflammation and pathogenicity.