Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1995 Sep 1;182(3):751–758. doi: 10.1084/jem.182.3.751

The p47phox mouse knock-out model of chronic granulomatous disease

PMCID: PMC2192153  PMID: 7650482

Abstract

Chronic granulomatous disease (CGD) is caused by a congenital defect in phagocyte reduced nicotinamide dinucleotide phosphate (NADPH) oxidase production of superoxide and related species. It is characterized by recurrent life-threatening bacterial and fungal infections and tissue granuloma formation. We have created a mouse model of CGD by targeted disruption of p47phox, one of the genes in which mutations cause human CGD. Identical to the case in human CGD, leukocytes from p47phox-/- mice produced no superoxide and killed staphylococci ineffectively. p47phox-/- mice developed lethal infections and granulomatous inflammation similar to those encountered in human CGD patients. This model mirrors human CGD and confirms a critical role for the phagocyte NADPH oxidase in mammalian host defense.

Full Text

The Full Text of this article is available as a PDF (2.3 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abo A., Pick E., Hall A., Totty N., Teahan C. G., Segal A. W. Activation of the NADPH oxidase involves the small GTP-binding protein p21rac1. Nature. 1991 Oct 17;353(6345):668–670. doi: 10.1038/353668a0. [DOI] [PubMed] [Google Scholar]
  2. Ament M. E., Ochs H. D. Gastrointestinal manifestations of chronic granulomatous disease. N Engl J Med. 1973 Feb 22;288(8):382–387. doi: 10.1056/NEJM197302222880802. [DOI] [PubMed] [Google Scholar]
  3. Baehner R. L., Nathan D. G. Quantitative nitroblue tetrazolium test in chronic granulomatous disease. N Engl J Med. 1968 May 2;278(18):971–976. doi: 10.1056/NEJM196805022781801. [DOI] [PubMed] [Google Scholar]
  4. Baron E. J., Proctor R. A. Elicitation of peritoneal polymorphonuclear neutrophils from mice. J Immunol Methods. 1982 Mar 26;49(3):305–313. doi: 10.1016/0022-1759(82)90130-2. [DOI] [PubMed] [Google Scholar]
  5. Bradfield J. F., Wagner J. E., Boivin G. P., Steffen E. K., Russell R. J. Epizootic fatal dermatitis in athymic nude mice due to Staphylococcus xylosus. Lab Anim Sci. 1993 Feb;43(1):111–113. [PubMed] [Google Scholar]
  6. Capecchi M. R. Altering the genome by homologous recombination. Science. 1989 Jun 16;244(4910):1288–1292. doi: 10.1126/science.2660260. [DOI] [PubMed] [Google Scholar]
  7. Casimir C. M., Bu-Ghanim H. N., Rodaway A. R., Bentley D. L., Rowe P., Segal A. W. Autosomal recessive chronic granulomatous disease caused by deletion at a dinucleotide repeat. Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2753–2757. doi: 10.1073/pnas.88.7.2753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Clark R. A., Malech H. L., Gallin J. I., Nunoi H., Volpp B. D., Pearson D. W., Nauseef W. M., Curnutte J. T. Genetic variants of chronic granulomatous disease: prevalence of deficiencies of two cytosolic components of the NADPH oxidase system. N Engl J Med. 1989 Sep 7;321(10):647–652. doi: 10.1056/NEJM198909073211005. [DOI] [PubMed] [Google Scholar]
  9. Dinauer M. C., Pierce E. A., Bruns G. A., Curnutte J. T., Orkin S. H. Human neutrophil cytochrome b light chain (p22-phox). Gene structure, chromosomal location, and mutations in cytochrome-negative autosomal recessive chronic granulomatous disease. J Clin Invest. 1990 Nov;86(5):1729–1737. doi: 10.1172/JCI114898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ding A. H., Nathan C. F., Stuehr D. J. Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production. J Immunol. 1988 Oct 1;141(7):2407–2412. [PubMed] [Google Scholar]
  11. Doetschman T. C., Eistetter H., Katz M., Schmidt W., Kemler R. The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. J Embryol Exp Morphol. 1985 Jun;87:27–45. [PubMed] [Google Scholar]
  12. Eisenhauer P. B., Lehrer R. I. Mouse neutrophils lack defensins. Infect Immun. 1992 Aug;60(8):3446–3447. doi: 10.1128/iai.60.8.3446-3447.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Forrest C. B., Forehand J. R., Axtell R. A., Roberts R. L., Johnston R. B., Jr Clinical features and current management of chronic granulomatous disease. Hematol Oncol Clin North Am. 1988 Jun;2(2):253–266. [PubMed] [Google Scholar]
  14. Gallin J. I., Buescher E. S. Abnormal regulation of inflammatory skin responses in male patients with chronic granulomatous disease. Inflammation. 1983 Sep;7(3):227–232. doi: 10.1007/BF00917259. [DOI] [PubMed] [Google Scholar]
  15. Gallin J. I., Buescher E. S., Seligmann B. E., Nath J., Gaither T., Katz P. NIH conference. Recent advances in chronic granulomatous disease. Ann Intern Med. 1983 Nov;99(5):657–674. doi: 10.7326/0003-4819-99-5-657. [DOI] [PubMed] [Google Scholar]
  16. Gallin J. I., Bujak J. S., Patten E., Wolff S. M. Granulocyte function in the Chediak-Higashi syndrome of mice. Blood. 1974 Feb;43(2):201–206. [PubMed] [Google Scholar]
  17. Gallin J. I., Malech H. L. Update on chronic granulomatous diseases of childhood. Immunotherapy and potential for gene therapy. JAMA. 1990 Mar 16;263(11):1533–1537. [PubMed] [Google Scholar]
  18. Gifford R. H., Malawista S. E. A simple rapid micromethod for detecting chronic granulomatous disease of childhood. J Lab Clin Med. 1970 Mar;75(3):511–519. [PubMed] [Google Scholar]
  19. Henderson W. R., Klebanoff S. J. Leukotriene production and inactivation by normal, chronic granulomatous disease and myeloperoxidase-deficient neutrophils. J Biol Chem. 1983 Nov 25;258(22):13522–13527. [PubMed] [Google Scholar]
  20. Jackson S. H., Malech H. L., Kozak C. A., Lomax K. J., Gallin J. I., Holland S. M. Cloning and functional expression of the mouse homologue of p47phox. Immunogenetics. 1994;39(4):272–275. doi: 10.1007/BF00188790. [DOI] [PubMed] [Google Scholar]
  21. Johnson K. J., Ward P. A. Role of oxygen metabolites in immune complex injury of lung. J Immunol. 1981 Jun;126(6):2365–2369. [PubMed] [Google Scholar]
  22. Leto T. L., Adams A. G., de Mendez I. Assembly of the phagocyte NADPH oxidase: binding of Src homology 3 domains to proline-rich targets. Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10650–10654. doi: 10.1073/pnas.91.22.10650. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Leto T. L., Lomax K. J., Volpp B. D., Nunoi H., Sechler J. M., Nauseef W. M., Clark R. A., Gallin J. I., Malech H. L. Cloning of a 67-kD neutrophil oxidase factor with similarity to a noncatalytic region of p60c-src. Science. 1990 May 11;248(4956):727–730. doi: 10.1126/science.1692159. [DOI] [PubMed] [Google Scholar]
  24. Lomax K. J., Leto T. L., Nunoi H., Gallin J. I., Malech H. L. Minor errors in two published sequences. Science. 1989 Nov 24;246(4933):987–987. doi: 10.1126/science.2587992. [DOI] [PubMed] [Google Scholar]
  25. Mouy R., Fischer A., Vilmer E., Seger R., Griscelli C. Incidence, severity, and prevention of infections in chronic granulomatous disease. J Pediatr. 1989 Apr;114(4 Pt 1):555–560. doi: 10.1016/s0022-3476(89)80693-6. [DOI] [PubMed] [Google Scholar]
  26. Murray H. W., Teitelbaum R. F. L-arginine-dependent reactive nitrogen intermediates and the antimicrobial effect of activated human mononuclear phagocytes. J Infect Dis. 1992 Mar;165(3):513–517. doi: 10.1093/infdis/165.3.513. [DOI] [PubMed] [Google Scholar]
  27. Nathan C. F., Cohn Z. A. Antitumor effects of hydrogen peroxide in vivo. J Exp Med. 1981 Nov 1;154(5):1539–1553. doi: 10.1084/jem.154.5.1539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ochs H. D., Igo R. P. The NBT slide test: a simple screening method for detecting chronic granulomatous disease and female carriers. J Pediatr. 1973 Jul;83(1):77–82. doi: 10.1016/s0022-3476(73)80316-6. [DOI] [PubMed] [Google Scholar]
  29. Parkos C. A., Dinauer M. C., Walker L. E., Allen R. A., Jesaitis A. J., Orkin S. H. Primary structure and unique expression of the 22-kilodalton light chain of human neutrophil cytochrome b. Proc Natl Acad Sci U S A. 1988 May;85(10):3319–3323. doi: 10.1073/pnas.85.10.3319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Pollock J. D., Williams D. A., Gifford M. A., Li L. L., Du X., Fisherman J., Orkin S. H., Doerschuk C. M., Dinauer M. C. Mouse model of X-linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production. Nat Genet. 1995 Feb;9(2):202–209. doi: 10.1038/ng0295-202. [DOI] [PubMed] [Google Scholar]
  31. Ramírez-Solis R., Rivera-Pérez J., Wallace J. D., Wims M., Zheng H., Bradley A. Genomic DNA microextraction: a method to screen numerous samples. Anal Biochem. 1992 Mar;201(2):331–335. doi: 10.1016/0003-2697(92)90347-a. [DOI] [PubMed] [Google Scholar]
  32. Roos D. The genetic basis of chronic granulomatous disease. Immunol Rev. 1994 Apr;138:121–157. doi: 10.1111/j.1600-065x.1994.tb00850.x. [DOI] [PubMed] [Google Scholar]
  33. Royer-Pokora B., Kunkel L. M., Monaco A. P., Goff S. C., Newburger P. E., Baehner R. L., Cole F. S., Curnutte J. T., Orkin S. H. Cloning the gene for an inherited human disorder--chronic granulomatous disease--on the basis of its chromosomal location. Nature. 1986 Jul 3;322(6074):32–38. doi: 10.1038/322032a0. [DOI] [PubMed] [Google Scholar]
  34. Volpp B. D., Nauseef W. M., Donelson J. E., Moser D. R., Clark R. A. Cloning of the cDNA and functional expression of the 47-kilodalton cytosolic component of human neutrophil respiratory burst oxidase. Proc Natl Acad Sci U S A. 1989 Sep;86(18):7195–7199. doi: 10.1073/pnas.86.18.7195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Vowells S. J., Sekhsaria S., Malech H. L., Shalit M., Fleisher T. A. Flow cytometric analysis of the granulocyte respiratory burst: a comparison study of fluorescent probes. J Immunol Methods. 1995 Jan 13;178(1):89–97. doi: 10.1016/0022-1759(94)00247-t. [DOI] [PubMed] [Google Scholar]
  36. Walther M. M., Malech H., Berman A., Choyke P., Venzon D. J., Linehan W. M., Gallin J. I. The urological manifestations of chronic granulomatous disease. J Urol. 1992 May;147(5):1314–1318. doi: 10.1016/s0022-5347(17)37552-3. [DOI] [PubMed] [Google Scholar]
  37. Williamson P. R., Kwon-Chung K. J., Gallin J. I. Successful treatment of Paecilomyces varioti infection in a patient with chronic granulomatous disease and a review of Paecilomyces species infections. Clin Infect Dis. 1992 May;14(5):1023–1026. doi: 10.1093/clinids/14.5.1023. [DOI] [PubMed] [Google Scholar]
  38. Xie Q. W., Cho H. J., Calaycay J., Mumford R. A., Swiderek K. M., Lee T. D., Ding A., Troso T., Nathan C. Cloning and characterization of inducible nitric oxide synthase from mouse macrophages. Science. 1992 Apr 10;256(5054):225–228. doi: 10.1126/science.1373522. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES