title: Reactive oxygen species produced by the NADPH oxidase 2 complex in monocytes protect mice from bacterial infections.
abstract: Chronic granulomatous disease (CGD) is an inherited disorder characterized by recurrent life-threatening bacterial and fungal infections. CGD results from defective production of reactive oxygen species by phagocytes caused by mutations in genes encoding the NADPH oxidase 2 (NOX2) complex subunits. Mice with a spontaneous mutation in Ncf1, which encodes the NCF1 (p47(phox)) subunit of NOX2, have defective phagocyte NOX2 activity. These mice occasionally develop local spontaneous infections by Staphylococcus xylosus or by the common CGD pathogen Staphylococcus aureus. Ncf1 mutant mice were more susceptible to systemic challenge with these bacteria than were wild-type mice. Transgenic Ncf1 mutant mice harboring the wild-type Ncf1 gene under the human CD68 promoter (MN(+) mice) gained the expression of NCF1 and functional NOX2 activity specifically in monocytes/macrophages, although minimal NOX2 activity was also detected in some CD11b(+)Ly6G(+) cells defined as neutrophils. MN(+) mice did not develop spontaneous infection and were more resistant to administered staphylococcal infections compared with MN(-) mice. Most strikingly, MN(+) mice survived after being administered Burkholderia cepacia, an opportunistic pathogen in CGD patients, whereas MN(-) mice died. Thus, monocyte/macrophage expression of functional NCF1 protected against spontaneous and administered bacterial infections.
authors.affiliation: Medical Inflammation Research, Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17177, Sweden.
authors.forename: Angela
authors.initials: A
authors.lastname: Pizzolla
authors.forename: Malin
authors.initials: M
authors.lastname: Hultqvist
authors.forename: Bo
authors.initials: B
authors.lastname: Nilson
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Grimm
authors.forename: Tove
authors.initials: T
authors.lastname: Eneljung
authors.forename: Ing-Marie
authors.initials: IM
authors.lastname: Jonsson
authors.forename: Margareta
authors.initials: M
authors.lastname: Verdrengh
authors.forename: Tiina
authors.initials: T
authors.lastname: Kelkka
authors.forename: Inger
authors.initials: I
authors.lastname: Gjertsson
authors.forename: Brahm H
authors.initials: BH
authors.lastname: Segal
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D019121:Burkholderia Infections / Q000201:enzymology / Q000382:microbiology / Q000517:prevention & control; D016956:Burkholderia cepacia / Q000276:immunology; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000201:enzymology* / Q000276:immunology / Q000382:microbiology*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000096:biosynthesis* / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013203:Staphylococcal Infections / Q000201:enzymology / Q000382:microbiology / Q000517:prevention & control*
chemical_list: D000900:Anti-Bacterial Agents; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1