GenTransOx

Horizontal gene transfer (HGT) is a major contributor to the spreading of new genetic variants within a bacterial population and thus to its genetic diversity. HGT is therefore critical for the capacity of microorganisms to adapt to environmental changes or to colonise new niches. In pathogens HGT also plays a major role in the spreading of antibacterial resistance genes. Antibiotic resistance is a huge concern in the treatment of bacterial infections and represents an alarming risk to human health in the coming years. The human gastric pathogen Helicobacter pylori is until now the only bacterium recognised as a class 1 carcinogen and is part of the recent WHO list of antibiotic-resistant “priority pathogens” that pose the greatest threat to human health. H. pylori colonises the stomach of half of the human population worldwide causing chronic gastritis that can evolve into ulcers or cancer that are responsible for 800,000 deaths per year. H. pylori genome presents high mutation rates leading to an amazing genetic diversity most likely contributing to the capacity of H. pylori to persistently colonise large and heterogeneous human populations. In H. pylori, natural transformation, i.e acquisition of exogenous DNA by a cell, is the main HGT mechanism that, together with very efficient recombination systems, results in the rapid spreading of the new alleles. This includes dissemination of antibiotic resistance markers which, in H. pylori, are restricted to chromosomal mutations. Given that H. pylori is the sole stable coloniser of the stomach and that its genetic variability is not restricted to cases of multiple H. pylori infections, the origin of this spectacular genomic variability has been a fascinating question since its discovery. Our project aims at elucidating the role of HGT in the propagation of new alleles in H. pylori using both in vitro cultures and an animal model. We want to assess the importance of oxidative stress in the acquisition and spread of genetic markers, in particular antibiotic resistant genes. Growing H. pylori are spiral-shaped and can evolve into another less studied spherical form, the coccoids. Coccoids have been observed in the stomach of patients and are induced during stationary phase culture or in response to an oxidative stress. Their role is poorly understood and recent results of the two project partners indicate that they are most probably dormant bacterial forms. A hypothesis that we will test with this project is that oxidative stress through the induction of coccoids contributes to H. pylori genetic diversity by acting as a reservoir of damaged or mutated DNA. To tackle these questions, we will combine the complementary knowhow of the two participating laboratories that, in a recent collaboration, have obtained promising preliminary data. The results we expect from this project should contribute to a better understanding of the mechanisms underlying the genome plasticity of H. pylori, one of the most genetically variable bacterial species described so far. They will also shed light on the role of coccoids, proposed to be a dormant viable form of H. pylori. In the long term, the comprehension of the process of HGT during H. pylori infection that affects half of the world population could be the basis to the development of new strategies to avoid the spreading of antibiotic resistance, a major Public Health issue.