AUTHOR=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 

TITLE=Hydrogen Peroxide Affects Growth of S. aureus Through Downregulation of Genes Involved in Pyrimidine Biosynthesis

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.673985

DOI=10.3389/fimmu.2021.673985

ISSN=1664-3224

ABSTRACT=<p>Reactive oxygen species (ROS) play a crucial role in the cellular defense against <italic>S. aureus</italic>, as evidenced by the importance of this pathogen in patients lacking the ROS-generating phagocyte NADPH oxidase NOX2. ROS concentrations required to kill <italic>S. aureus in vitro</italic> are much higher than those found in the phagosome. We therefore hypothesized that sublethal ROS concentrations may play a role in <italic>S. aureus</italic> gene dysregulation and investigated the <italic>in vitro</italic> transcriptomic response of <italic>S. aureus</italic> to sublethal concentrations of hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>). 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 <italic>carA</italic>, a gene involved in pyrimidine synthesis, led to a significant growth defect and to an increased sensitivity of <italic>S. aureus</italic> to added H<sub>2</sub>O<sub>2</sub>. The phenotype of the <italic>carA</italic> mutant could be reversed through supplementation with the pyrimidine precursor uracil, or with a multicopy vector encoding <italic>carA</italic>. As opposed to the impact of ROS on extracellular survival, <italic>carA</italic> 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 <italic>S. aureus</italic>, allowing colonization through intracellular survival, while decreasing the risk of killing the host through dampened extracellular growth.</p>