Host Nitric Oxide Disrupts Microbial Cell-to-Cell Communication to Inhibit Staphylococcal Virulence

Cell Host Microbe. 2018 May 9;23(5):594-606.e7. doi: 10.1016/j.chom.2018.04.001.


Staphylococcus aureus is a commensal bacterium that can asymptomatically colonize its host but also causes invasive infections. Quorum sensing regulates S. aureus virulence and the transition from a commensal to a pathogenic organism. However, little is known about how host innate immunity affects interbacterial communication. We show that nitric oxide suppresses staphylococcal virulence by targeting the Agr quorum sensing system. Nitric oxide-mediated inhibition occurs through direct modification of cysteine residues C55, C123, and C199 of the AgrA transcription factor. Cysteine modification decreases AgrA promoter occupancy as well as transcription of the agr operon and quorum sensing-activated toxin genes. In a staphylococcal pneumonia model, mice lacking inducible nitric oxide synthase develop more severe disease with heightened mortality and proinflammatory cytokine responses. In addition, staphylococcal α-toxin production increases in the absence of nitric oxide or nitric oxide-sensitive AgrA cysteine residues. Our findings demonstrate an anti-virulence mechanism for nitric oxide in innate immunity.

Keywords: S. aureus; bacterial pathogenesis; host defense; innate immunity; nitric oxide; quorum sensing; virulence.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bacterial Proteins / metabolism
  • Bacterial Toxins / metabolism
  • Cell Communication / immunology*
  • Cell Communication / physiology*
  • Cysteine
  • Cytokines / metabolism
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Bacterial / drug effects
  • Hemolysin Proteins / metabolism
  • Host-Pathogen Interactions / immunology*
  • Host-Pathogen Interactions / physiology*
  • Immunity, Innate
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide / antagonists & inhibitors*
  • Nitric Oxide Synthase Type II / genetics
  • Operon
  • Pneumonia, Staphylococcal / metabolism
  • Pneumonia, Staphylococcal / pathology
  • Promoter Regions, Genetic / drug effects
  • Quorum Sensing / drug effects
  • Quorum Sensing / genetics
  • Staphylococcal Infections / microbiology
  • Staphylococcus / drug effects*
  • Staphylococcus / pathogenicity*
  • Staphylococcus aureus / drug effects
  • Staphylococcus aureus / pathogenicity
  • Trans-Activators / metabolism
  • Transcription Factors / drug effects
  • Virulence / drug effects


  • Agr protein, Staphylococcus aureus
  • Bacterial Proteins
  • Bacterial Toxins
  • Cytokines
  • Hemolysin Proteins
  • Trans-Activators
  • Transcription Factors
  • staphylococcal alpha-toxin
  • Nitric Oxide
  • Nitric Oxide Synthase Type II
  • Cysteine