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. Lesions will be introduced that either correspond to previously identified mutations in humans or that incapacitate systems probably involved in host defense. Therefore, this project relies upon a thorough understanding of the molecular and functional organization of the NADPH oxidase system and the mutations which disable it. Further, the dissection of specific phenotypes associated with defined genotypes may provide insight into the importance of certain functional domains of the genes of the NADPH oxidase and indicate which sites are most informative for further study. We have used the NADPH oxidase system as a paradigm for the creation of mice with a genetic defect similar to one found in humans, chronic granulomatous disease (CGD). To this end, we have cloned, sequenced, and functionally expressed the cDNA of the murine homolog of the human p47phox gene. We have cloned, partially sequenced, characterized, and disrupted genomic fragments from both the p47phox and gp91phox genes in preparation for re-insertion into the mouse genome. Disruption of these genes will provide the bases for a murine model of the autosomal recessive and X-linked forms of CGD, respectively. Culture of the embryonal stem cells which will provide the targets necessary to this project is now established in the laboratory. In the course of this work we have 1) identified two introns in the murine p47phox gene which are not found in the human gene, 2) characterized two novel mutations in a large family with CGD related granulomatous colitis, 3) identified and partially characterized a family with ineffective granulomatous inflammation as demonstrated by disseminated Mycobacterium avium infection, 4) overcome the inflammatory defect in the family with disseminated Mycobacterium avium infection by treatment with interferon gamma.
| 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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