This project is directed at understanding the role of specific enzyme systems in generating and maintaining host immunity. The approach taken involves the creation of mice with discrete defects in host defenses by using homologous recombination of DNA into the host genome to disrupt relevant genes. We have manipulated the NADPH oxidase system to create mice with a genetic defect similar to one found in humans, chronic granulomatous disease (CGD). This project relies upon a thorough understanding of the molecular and functional organization of the NADPH oxidase system and the mutations which disable it. We have created a mouse deficient in the p47phox gene product, a necessary component of the NADPH oxidase complex. In the absence of this gene product, mice, like humans, fail to produce phagocyte superoxide and metabolites. In addition, these mice show a benefit to the administration of prophylactic interferon gamma in terms of the prevention of infections. Therefore, this mouse system presents a model in which to investigate interferon gamma~s effect and mechanism of action in infection prophylaxis. Creation of a mouse model of CGD has provided us with the opportunity to investigate specific mechanisms, interventions, and therapies, including interferon gamma and gene therapy. Since the NADPH oxidase has been implicated the genesis of other conditions, such as atherosclerosis and reperfusion injury, this mouse will provide a valuable tool for the determination of its contribution in these settings as well.
| Falcone, E Liana; Petts, Jennifer R; Fasano, Mary Beth et al. (2016) Methylotroph Infections and Chronic Granulomatous Disease. Emerg Infect Dis 22:404-9 |
| Hsu, Amy P; Sowerwine, Kathryn J; Lawrence, Monica G et al. (2013) Intermediate phenotypes in patients with autosomal dominant hyper-IgE syndrome caused by somatic mosaicism. J Allergy Clin Immunol 131:1586-93 |
| Kuhns, Douglas B; Alvord, W Gregory; Heller, Theo et al. (2010) Residual NADPH oxidase and survival in chronic granulomatous disease. N Engl J Med 363:2600-10 |
| Cortes, Lizette M; Mattapallil, Mary J; Silver, Phyllis B et al. (2008) Repertoire analysis and new pathogenic epitopes of IRBP in C57BL/6 (H-2b) and B10.RIII (H-2r) mice. Invest Ophthalmol Vis Sci 49:1946-56 |
| Ling, Jennifer C; Freeman, Alexandra F; Gharib, Ahmed M et al. (2007) Coronary artery aneurysms in patients with hyper IgE recurrent infection syndrome. Clin Immunol 122:255-8 |
| Freeman, Alexandra F; Collura-Burke, Christina J; Patronas, Nicholas J et al. (2007) Brain abnormalities in patients with hyperimmunoglobulin E syndrome. Pediatrics 119:e1121-5 |
| Greenberg, David E; Porcella, Stephen F; Zelazny, Adrian M et al. (2007) Genome sequence analysis of the emerging human pathogenic acetic acid bacterium Granulibacter bethesdensis. J Bacteriol 189:8727-36 |
| Woellner, Cristina; Schaffer, Alejandro A; Puck, Jennifer M et al. (2007) The hyper IgE syndrome and mutations in TYK2. Immunity 26:535;author reply 536 |
| Doerries, Carola; Grote, Karsten; Hilfiker-Kleiner, Denise et al. (2007) Critical role of the NAD(P)H oxidase subunit p47phox for left ventricular remodeling/dysfunction and survival after myocardial infarction. Circ Res 100:894-903 |
| Siddiqui, Sophia; Anderson, Victoria L; Hilligoss, Diane M et al. (2007) Fulminant mulch pneumonitis: an emergency presentation of chronic granulomatous disease. Clin Infect Dis 45:673-81 |
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