The RpoB H{481}Y rifampicin resistance mutation and an active stringent response reduce virulence and increase resistance to innate immune responses in Staphylococcus aureus

Wei Gao, David Cameron, John Keith Davies, Xenia Polyxeni Kostoulias, Justin Stepnell, Kellie Louise Tuck, Michael R Yeaman, Anton Yariv Peleg, Timothy Paul Stinear, Benjamin Peter Howden

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47 Citations (Scopus)

Abstract

The occurrence of mutations in methicillin-resistant Staphylococcus aureus (MRSA) during persistent infection leads to antimicrobial resistance but may also impact host-pathogen interactions. Here, we investigate the host-pathogen consequences of 2 mutations arising in clinical MRSA during persistent infection: RpoB H(4)(8)(1)Y, which is linked to rifampicin resistance, and RelA F(1)(2)(8)Y, which is associated with an active stringent response. Allelic exchange experiments showed that both mutations cause global transcriptional changes, leading to upregulation of capsule production, with attenuated virulence in a murine bacteremia model and reduced susceptibility to both antimicrobial peptides and whole-blood killing. Disruption of capsule biosynthesis reversed these impacts on innate immune function. These data clearly link MRSA persistence and reduced virulence to the same mechanisms that alter antimicrobial susceptibility. Our study highlights the wider consequences of suboptimal antimicrobial use, where drug resistance and immune escape mechanisms coevolve, thus increasing the likelihood of treatment failure.
Original languageEnglish
Pages (from-to)929 - 939
Number of pages11
JournalJournal of Infectious Diseases
Volume207
Issue number6
DOIs
Publication statusPublished - 2013

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