1. Hydrogen Peroxide Affects Growth of S. aureus Through Downregulation of Genes Involved in Pyrimidine Biosynthesis
- Author
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Buvelot, Hélène, Roth, Myriam, Jaquet, Vincent, Lozkhin, Andrey, Renzoni, Adriana, Bonetti, Eve-Julie, Gaia, Nadia, Laumay, Floriane, Mollin, Michéle, Stasia, Marie-José, Schrenzel, Jacques, François, Patrice, Krause, Karl-Heinz, Department of Pathology and Immunology [Geneva, Switzerland] (Clinical Pathology Division), Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], Service of Infectious Diseases [Geneva, Switzerland], Geneva University Hospital (HUG), Service of infectious diseases, Hôpitaux Universitaires de Genève (HUG), CGD Diagnosis and Research Centre (CDiReC), Centre Hospitalier Universitaire [Grenoble] (CHU), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Centre Diagnostic et Recherche sur la Granulomatose septique chronique (CDiReC), CHUGA, University of Geneva [Switzerland]-Geneva University Hospitals - HUG [Switzerland], and Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes)
- Subjects
Staphylococcus aureus ,[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM] ,Immunology ,Down-Regulation ,hydrogen peroxide ,Gene Expression Regulation, Bacterial ,S. aureus ,pyrimidine metabolism ,Pyrimidines ,Bacterial Proteins ,neutrophils ,carA ,Immunology and Allergy ,Humans ,Reactive Oxygen Species ,Cells, Cultured ,Original Research - Abstract
International audience; Reactive oxygen species (ROS) play a crucial role in the cellular defense against S. aureus , as evidenced by the importance of this pathogen in patients lacking the ROS-generating phagocyte NADPH oxidase NOX2. ROS concentrations required to kill S. aureus in vitro are much higher than those found in the phagosome. We therefore hypothesized that sublethal ROS concentrations may play a role in S. aureus gene dysregulation and investigated the in vitro transcriptomic response of S. aureus to sublethal concentrations of hydrogen peroxide (H 2 O 2 ). A striking observation of these experiments was a coordinated and massive downregulation of genes involved in pyrimidine metabolism. Using transposon insertion mutants, we demonstrated that deletion of carA , a gene involved in pyrimidine synthesis, led to a significant growth defect and to an increased sensitivity of S. aureus to added H 2 O 2 . The phenotype of the carA mutant could be reversed through supplementation with the pyrimidine precursor uracil, or with a multicopy vector encoding carA . As opposed to the impact of ROS on extracellular survival, carA deletion did not affect the intracellular survival in neutrophils. Our results raise the possibility that ROS-dependent downregulation of pyrimidine metabolism might be a survival strategy of S. aureus , allowing colonization through intracellular survival, while decreasing the risk of killing the host through dampened extracellular growth.
- Published
- 2021