Abstract
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 in vivo. Here we investigate the role of copper hypertolerance in methicillin-resistant Staphylococcus aureus (MRSA). We show that a copper hypertolerance operon (copB-mco), carried on a mobile genetic element (MGE), is prevalent in a collection of invasive S. aureus strains and more widely among clonal complex 22, 30, and 398 strains. The copB and mco genes encode a copper efflux pump and a multicopper oxidase, respectively. Isogenic mutants lacking copB or mco had impaired growth in subinhibitory concentrations of copper. Transfer of a copB-mco-carrying
plasmid to a naive clinical isolate resulted in a gain of copper
hypertolerance and enhanced bacterial survival inside primed
macrophages. The copB and mco genes were upregulated
within infected macrophages, and their expression was dependent on the
copper-sensitive operon repressor CsoR. Isogenic copB and mco
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 S. aureus that are better equipped to resist killing by host immune cells.
Original language | English |
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Article number | e00550-18 |
Number of pages | 15 |
Journal | mBio |
Volume | 9 |
Issue number | 5 |
DOIs | |
Publication status | Published - 16 Oct 2018 |
Keywords
- MRSA
- P-type ATPase
- Staphylococcus aureus
- Copper tolerance
- Macrophages
- Metals
- Mobile genetic elements
- Multicopper oxidase
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Matthew Holden
- School of Medicine - Director of Impact, Professor
- Biomedical Sciences Research Complex
- St Andrews Bioinformatics Unit
- Infection and Global Health Division
Person: Academic