Proceedings of the National Academy of Sciences of the United States of America
Quorum sensing triggers virulence factor expression in medically important bacterial pathogens in response to a density-dependent increase in one or more autoinducing pheromones. Here, we show that phagocyte-derived oxidants target these autoinducers for inactivation as an innate defense mechanism of the host. In a skin infection model, expression of phagocyte NADPH oxidase, myeloperoxidase, or inducible nitric oxide synthase was critical for defense against a quorum-sensing pathogen, Staphylococcus aureus, but not for defense against a quorum sensing-deficient mutant. A virulence-inducing peptide of S. aureus was inactivated in vitro and in vivo by reactive oxygen and nitrogen intermediates, including HOCl and ONOO(-). Inactivation of the autoinducer prevented both the up-regulation of virulence gene expression and the downstream sequelae. MS analysis of the inactivated peptide demonstrated that oxidation of the C-terminal methionine was primarily responsible for loss of activity. Treatment of WT but not NADPH oxidase-deficient mice with N-acetyl methionine to scavenge the inhibitory oxidants increased in vivo quorum sensing independently of the bacterial burden at the site of infection. Thus, oxidant-mediated inactivation of an autoinducing peptide from S. aureus is a critical innate defense mechanism against infection with this pathogen.
Rothfork, Jacob M.; Timmins, Graham S.; Harris, Michael N.; Chen, Xian; Lusis, Aldons J.; Otto, Michael; Cheung, Ambrose L.; and Gresham, Hattie D., "Inactivation of a Bacterial Virulence Pheromone by Phagocyte-Derived Oxidants: New Role for the NADPH Oxidase in Host Defense" (2004). Open Dartmouth: Faculty Open Access Articles. 1702.