22Pathogens are exposed to toxic levels of copper during infection and copper tolerance 23 may be a general virulence mechanism used by bacteria to resist host defences. In support of 24 this, inactivation of copper-exporter genes has been found to reduce the virulence of bacterial 25 pathogens in vivo. Here we investigate the role of copper-hypertolerance in methicillin 26 resistant Staphylococcus aureus. We show that a copper-hypertolerance locus (copB-mco), 27 carried on a mobile genetic element, is prevalent in a collection of invasive S. aureus strains 28 and more widely among clonal complex 22, 30 and 398 strains. The copB and mco genes 29 encode a copper efflux pump and a multicopper oxidase, respectively. Isogenic mutants 30 lacking copB or mco had impaired growth in subinhibitory concentrations of copper. Transfer 31 of a copB-mco encoding plasmid to a naive clinical isolate resulted in a gain of copper-32 hypertolerance and enhanced bacterial survival inside primed macrophages. The copB and 33 mco genes were upregulated within infected macrophages and their expression was 34 dependent on the copper sensitive operon repressor CsoR. Isogenic copB and mco mutants 35were impaired in their ability to persist intracellularly in macrophages and were less resistant 36 to phagocytic killing in human blood than the parent strain. The importance of copper-37 regulated genes in resistance to phagocytic killing was further elaborated using mutants 38 expressing a copper-insensitive variant of CsoR. Our findings suggest that the gain of mobile 39 genetic elements carrying copper-hypertolerance genes contributes to the evolution of 40 virulent strains of S. aureus, better equipped to resist killing by host immune cells. 41 42 43
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