Mobile-Genetic-Element-Encoded Hypertolerance to Copper Protects Staphylococcus aureus from Killing by Host Phagocytes.

Pathogens are exposed to toxic levels of copper during infection, and copper tolerance may be a general virulence mechanism used by bacteria to resist host defenses. In support of this, inactivation of copper exporter genes has been found to reduce the virulence of bacterial pathogens Here we investigate the role of copper hypertolerance in methicillin-resistant (MRSA). We show that a copper hypertolerance operon (), carried on a mobile genetic element (MGE), is prevalent in a collection of invasive strains and more widely among clonal complex 22, 30, and 398 strains. The and genes encode a copper efflux pump and a multicopper oxidase, respectively. Isogenic mutants lacking or had impaired growth in subinhibitory concentrations of copper. Transfer of a carrying plasmid to a naive clinical isolate resulted in a gain of copper hypertolerance and enhanced bacterial survival inside primed macrophages. The and genes were upregulated within infected macrophages, and their expression was dependent on the copper-sensitive operon repressor CsoR. Isogenic and mutants were impaired in their ability to persist intracellularly in macrophages and were less resistant to phagocytic killing in human blood than the parent strain. The importance of copper-regulated genes in resistance to phagocytic killing was further elaborated using mutants expressing a copper-insensitive variant of CsoR. Our findings suggest that the gain of mobile genetic elements carrying copper hypertolerance genes contributes to the evolution of virulent strains of that are better equipped to resist killing by host immune cells. Methicillin-resistant (MRSA) poses a substantial threat to human health worldwide and evolves rapidly by acquiring mobile genetic elements, such as plasmids. Here we investigate how the - copper hypertolerance operon carried on a mobile genetic element contributes to the virulence potential of clinical isolates of MRSA. Copper is a key component of innate immune bactericidal defenses. Here we show that copper hypertolerance genes enhance the survival of inside primed macrophages and in whole human blood. The and genes are carried by clinical isolates responsible for invasive infections across Europe, and more broadly among three successful clonal lineages of Our findings show that a gain of copper hypertolerance genes increases the resistance of MRSA to phagocytic killing by host immune cells and imply that acquisition of this mobile genetic element can contribute to the success of MRSA.