| Title: | Inactivation of a bacterial virulence pheromone by phagocyte-derived oxidants: new role for the NADPH oxidase in host defense |
| Author(s): | Rothfork JM; Timmins GS; Harris MN; Chen X; Lusis AJ; Otto M; Cheung AL; Gresham HD; |
| Address: | "Research Service, Albuquerque Veterans Affairs Medical Center, Albuquerque, NM 87108, USA" |
| ISSN/ISBN: | 0027-8424 (Print) 1091-6490 (Electronic) 0027-8424 (Linking) |
| Abstract: | "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" |
| Keywords: | "Animals Gene Expression Regulation, Enzymologic/drug effects Hydrogen Peroxide/pharmacology Membrane Glycoproteins/deficiency/*genetics/metabolism Mice Mice, Knockout NADPH Oxidase 2 NADPH Oxidases/deficiency/*genetics/*metabolism Nitric Oxide Synthase/de;" |
| Notes: | "MedlineRothfork, Jacob M Timmins, Graham S Harris, Michael N Chen, Xian Lusis, Aldons J Otto, Michael Cheung, Ambrose L Gresham, Hattie D eng AI46615/AI/NIAID NIH HHS/ AI47441/AI/NIAID NIH HHS/ R01 AI047441/AI/NIAID NIH HHS/ HL30568/HL/NHLBI NIH HHS/ P01 HL030568/HL/NHLBI NIH HHS/ R01 AI046615/AI/NIAID NIH HHS/ Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S. 2004/09/09 Proc Natl Acad Sci U S A. 2004 Sep 21; 101(38):13867-72. doi: 10.1073/pnas.0402996101. Epub 2004 Sep 7" |
