Commensal bacteria augment Staphylococcus aureus infection by inactivation of phagocyte-derived reactive oxygen species

<i>Staphylococcus aureus </i>is a human commensal organism and opportunist pathogen, causing potentially fatal disease. The presence of non-pathogenic microflora or their components, at the point of infection, dramatically increases <i>S. aureus</i> pathogenicity, a process termed augmentation. Augmentation is associated with macrophage interaction but by a hitherto unknown mechanism. Here, we demonstrate a breadth of cross-kingdom microorganisms can augment <i>S. aureus</i> disease and that pathogenesis of <i>Enterococcus faecalis </i>can also be augmented. Co-administration of augmenting material also forms an efficacious vaccine model for <i>S. aureus</i>. <i>In vitro</i>, augmenting material protects<i> S. aureus </i>directly<i> </i>from reactive oxygen species (ROS), which correlates with <i>in vivo </i>studies where augmentation restores full virulence to the ROS-susceptible, attenuated mutant <i>katA ahpC</i>. At the cellular level, augmentation increases bacterial survival within macrophages via amelioration of ROS, leading to proliferation and escape. We have defined the molecular basis for augmentation that represents an important aspect of the initiation of infection. <br>Animal work in the UK was performed in accordance with the Animal (Scientific Procedures) Act 1986. At the University of Sheffield, work was completed under project licences P3BFD6DB9 and PPL 40/3699 for murine work, or P1A4A7A5E for zebrafish work, with ethical approval from the University of Sheffield Local Ethical Review Panel. At Imperial College London, work was conducted under licence P4C824899 with approval from the Imperial ethical review board. At INRAE, animal work was approved by the local ethics committee (COMETHEA or “Comité d’Ethique en Expérimentation Animale”, Centre de Recherche Ile de France - Jouy en Josas – Antony) under the registration numbers 15_08, and by the French Ministry of Higher Education and Research APAFIS #480-2015041518048149v1, where all animal experiments were performed in accordance with European directive 2010/63/EU. Animal experiments in Calgary were approved by the University of Calgary Animal Care Committee and were in compliance with the Canadian Council for Animal Care Guidelines (protocol nr. AC16-0148). MDMs were derived, with informed consent, from the blood of healthy volunteers, in accordance with guidelines from the South Sheffield Research Ethics Committee (07/Q2305/7). <br><br>