title: The RpoB H₄₈₁Y rifampicin resistance mutation and an active stringent response reduce virulence and increase resistance to innate immune responses in Staphylococcus aureus.
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 H₄₈₁Y, which is linked to rifampicin resistance, and RelA F₁₂₈Y, 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.
authors.affiliation: Infectious Diseases Department, Austin Centre for Infection Research, University of Melbourne, Australia.
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.forename: David R
authors.initials: DR
authors.lastname: Cameron
authors.forename: John K
authors.initials: JK
authors.lastname: Davies
authors.forename: Xenia
authors.initials: X
authors.lastname: Kostoulias
authors.forename: Justin
authors.initials: J
authors.lastname: Stepnell
authors.forename: Kellie L
authors.initials: KL
authors.lastname: Tuck
authors.forename: Michael R
authors.initials: MR
authors.lastname: Yeaman
authors.forename: Anton Y
authors.initials: AY
authors.lastname: Peleg
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Stinear
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Howden
mesh_terms: D000818:Animals; D016667:Bacterial Capsules / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012321:DNA-Directed RNA Polymerases / Q000235:genetics*; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D005260:Female; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000235:genetics* / Q000472:pathogenicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012293:Rifampin; D013203:Staphylococcal Infections / Q000276:immunology*; D051996:Transcription Factor RelA / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics*; D015854:Up-Regulation; D014774:Virulence / Q000235:genetics; D023084:alpha-Defensins / Q000494:pharmacology; D023083:beta-Defensins / Q000494:pharmacology
chemical_list: C106641:DEFB4A protein, human; D051996:Transcription Factor RelA; D023084:alpha-Defensins; D023083:beta-Defensins; C406413:human neutrophil peptide 1; D012321:DNA-Directed RNA Polymerases; C105078:RNA polymerase beta subunit; D012293:Rifampin