title: Retroviral-mediated gene transfer of gp91phox into bone marrow cells rescues defect in host defense against Aspergillus fumigatus in murine X-linked chronic granulomatous disease.
abstract: The X-linked form of chronic granulomatous disease (X-CGD), an inherited deficiency of the respiratory burst oxidase, results from mutations in the X-linked gene for gp91phox, the larger subunit of the oxidase cytochrome b. The goal of this study was to evaluate the impact of retroviral-mediated gene transfer of gp91phox on host defense against Aspergillus fumigatus in a murine model of X-CGD. Retrovirus vectors constructed using the murine stem cell virus (MSCV) backbone were used for gene transfer of the gp91phox cDNA into murine X-CGD bone marrow cells. Transduced cells were transplanted into lethally irradiated syngeneic X-CGD mice. After hematologic recovery, superoxide production, as monitored by the nitroblue tetrazolium (NBT) test, was detected in up to approximately 80% of peripheral blood neutrophils for at least 28 to 35 weeks after transplantation. Neutrophil expression of recombinant gp91phox and superoxide production were significantly less than wild-type neutrophils. However, 9 of 9 mice with approximately 50% to 80% NBT+ neutrophils after gene transfer did not develop lung disease after respiratory challenge with 150 to 500 A fumigatus spores, doses that produced disease in 16 of 16 control X-CGD mice. In X-CGD mice transplanted with mixtures of wild-type and X-CGD bone marrow, > or = 5% wild-type neutrophils were required for protection against A fumigatus challenge. These data suggest that expression of even low levels of recombinant gp91phox can substantially improve phagocyte function in X-CGD, although correction of very small percentage of phagocytes may not be sufficient for protection against A fumigatus.
authors.affiliation: Herman B Wells Center for Pediatric Research, Department of Pediatrics (Hematology-Oncology), James Whitcomb Riley Hospital for Children, Indiana University Medical Center, Indianapolis, USA.
authors.forename: H
authors.initials: H
authors.lastname: Björgvinsdóttir
authors.forename: C
authors.initials: C
authors.lastname: Ding
authors.forename: N
authors.initials: N
authors.lastname: Pech
authors.forename: M A
authors.initials: MA
authors.lastname: Gifford
authors.forename: L L
authors.initials: LL
authors.lastname: Li
authors.forename: M C
authors.initials: MC
authors.lastname: Dinauer
mesh_terms: D000818:Animals; D001228:Aspergillosis / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D001232:Aspergillus fumigatus; D018076:DNA, Complementary / Q000235:genetics; D004198:Disease Susceptibility; D005260:Female; D017988:Gammaretrovirus / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D006105:Granulomatous Disease, Chronic / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D016867:Immunocompromised Host; D008172:Lung Diseases, Fungal / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D009504:Neutrophils / Q000201:enzymology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016897:Respiratory Burst / Q000235:genetics; D014960:X Chromosome
chemical_list: D018076:DNA, Complementary; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases