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Title: The RpoB H₄₈₁Y rifampicin resistance mutation and an active stringent response reduce virulence and increase resistance to innate immune responses in Staphylococcus aureus.
Austin Authors: Gao, Wei;Cameron, David R;Davies, John K;Kostoulias, Xenia;Stepnell, Justin;Tuck, Kellie L;Yeaman, Michael R;Peleg, Anton Y;Stinear, Timothy P;Howden, Benjamin P 
Affiliation: Infectious Diseases Department, Austin Centre for Infection Research, University of Melbourne, Australia
Issue Date: 18-Dec-2012
Publication information: The Journal of Infectious Diseases 2012; 207(6): 929-39
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.
Gov't Doc #: 23255563
DOI: 10.1093/infdis/jis772
Type: Journal Article
Subjects: Animals
Bacterial Capsules.genetics.immunology.metabolism
DNA-Directed RNA Polymerases.genetics
Drug Resistance, Bacterial.genetics
Host-Pathogen Interactions.genetics.immunology
Immunity, Innate
Methicillin-Resistant Staphylococcus aureus.drug effects.genetics.pathogenicity
Mice, Inbred BALB C
Polymorphism, Single Nucleotide
Staphylococcal Infections.immunology
Transcription Factor RelA.genetics
Transcription, Genetic.genetics
Appears in Collections:Journal articles

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