Inactivation of a bacterial virulence pheromone by phagocyte-derived oxidants: new role for the NADPH oxidase in host defense.
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
JM
Research Service, Albuquerque Veterans Affairs Medical Center, Albuquerque, NM 87108, USA.
Timmins
Graham S
GS
Harris
Michael N
MN
Chen
Xian
X
Lusis
Aldons J
AJ
Otto
Michael
M
Cheung
Ambrose L
AL
Gresham
Hattie D
HD
D000818:Animals; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D016877:Oxidants / Q000494:pharmacology; D009195:Peroxidase; D010586:Phagocytes / Q000502:physiology*; D010675:Pheromones / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012320:RNA Polymerase III / Q000235:genetics; D013203:Staphylococcal Infections / Q000235:genetics / Q000503:physiopathology*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000472:pathogenicity* / Q000502:physiology; D014774:Virulence
D008562:Membrane Glycoproteins; D016877:Oxidants; D010675:Pheromones; D006861:Hydrogen Peroxide; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D012320:RNA Polymerase III