The RpoB H481Y Rifampicin Resistance Mutation and an Active Stringent Response Reduce Virulence and Increase Resistance to Innate Immune Responses in Staphylococcus aureus

• Published in: The Journal of infectious diseases Vol. 207; no. 6; pp. 929 - 939
• Main 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.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.03.2013
• Subjects: alpha-Defensins - pharmacology; Animals; Antimicrobials; BACTERIA; Bacterial Capsules - genetics; Bacterial Capsules - immunology; Bacterial Capsules - metabolism; Bacteriology; beta-Defensins - pharmacology; Biological and medical sciences; Capsules; DNA-Directed RNA Polymerases - genetics; Drug Resistance, Bacterial - genetics; Enzymes; Female; Fundamental and applied biological sciences. Psychology; Genes; Genetic mutation; Host-Pathogen Interactions - genetics; Host-Pathogen Interactions - immunology; Humans; Immunity, Innate; Infections; Infectious diseases; Killing; Major and Brief Reports; Medical sciences; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - genetics; Methicillin-Resistant Staphylococcus aureus - pathogenicity; Mice; Mice, Inbred BALB C; Microbiology; Miscellaneous; Phenotype; Polymorphism, Single Nucleotide; Polysaccharides; Rifampin; Staphylococcal Infections - immunology; Staphylococcus aureus; Transcription Factor RelA - genetics; Transcription, Genetic - genetics; Up-Regulation; Virulence; Virulence - genetics; Immune response; Virulence; Natural immunity; Infection; Stringent control; Resistance; Antibiotic; Rifampicin; Bacteria; Micrococcales; Micrococcaceae; Antituberculous agent; Protein synthesis inhibitor; Mutation; Antibacterial agent; Staphylococcus aureus
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jis772

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 481 Y, which is linked to rifampicin resistance, and RelA F 128 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.