Skip to main content
NCBI home page
Infection and Immunity logoLink to Infection and Immunity
. 1997 Feb;65(2):551–556. doi: 10.1128/iai.65.2.551-556.1997

Role of aspartic proteases in disseminated Candida albicans infection in mice.

K Fallon 1, K Bausch 1, J Noonan 1, E Huguenel 1, P Tamburini 1
PMCID: PMC176095  PMID: 9009312

Abstract

A murine model of disseminated candidiasis involving intranasal challenge with Candida albicans was developed and used to explore the role of C. albicans aspartic proteases as virulence factors during early dissemination. Pretreatment of neutropenic mice with the aspartic protease inhibitor pepstatin A by intraperitoneal injection afforded strong dose-dependent protection against a subsequent lethal intranasal dose of an aspartic protease-producing strain (ATCC 32354) of C. albicans. Administration of 0.6 mg of pepstatin A kg of body weight(-1) prior to challenge and on days 1 to 4 postchallenge resulted in 100% survival at day 15 postchallenge, whereas 100% of animals receiving saline had died by day 6. This effect was comparable to the dose-dependent protection obtained with amphotericin B, which resulted in 100% survival when administered at 0.1 mg kg(-1). The reduction in mortality afforded by pepstatin A correlated with its dose-dependent blockade of C. albicans numbers in the lungs, liver, and kidneys. By sharp contrast, no protection by pepstatin A was observed in mice challenged intravenously, and protection was markedly attenuated in mice given pepstatin A after intranasal challenge only. These data show the utility of pepstatin A in the prophylaxis of disseminated Candida infections and suggest that Candida aspartic proteases play an essential role early in dissemination.

Full Text

The Full Text of this article is available as a PDF (231.8 KB).

Selected References

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

  1. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  2. Cassone A., De Bernardis F., Mondello F., Ceddia T., Agatensi L. Evidence for a correlation between proteinase secretion and vulvovaginal candidosis. J Infect Dis. 1987 Nov;156(5):777–783. doi: 10.1093/infdis/156.5.777. [DOI] [PubMed] [Google Scholar]
  3. Chakrabarti A., Nayak N., Talwar P. In vitro proteinase production by Candida species. Mycopathologia. 1991 Jun;114(3):163–168. doi: 10.1007/BF00437209. [DOI] [PubMed] [Google Scholar]
  4. De Bernardis F., Agatensi L., Ross I. K., Emerson G. W., Lorenzini R., Sullivan P. A., Cassone A. Evidence for a role for secreted aspartate proteinase of Candida albicans in vulvovaginal candidiasis. J Infect Dis. 1990 Jun;161(6):1276–1283. doi: 10.1093/infdis/161.6.1276. [DOI] [PubMed] [Google Scholar]
  5. Dreyer R. N., Bausch K. M., Fracasso P., Hammond L. J., Wunderlich D., Wirak D. O., Davis G., Brini C. M., Buckholz T. M., König G. Processing of the pre-beta-amyloid protein by cathepsin D is enhanced by a familial Alzheimer's disease mutation. Eur J Biochem. 1994 Sep 1;224(2):265–271. doi: 10.1111/j.1432-1033.1994.00265.x. [DOI] [PubMed] [Google Scholar]
  6. Ghannoum M., Abu Elteen K. Correlative relationship between proteinase production, adherence and pathogenicity of various strains of Candida albicans. J Med Vet Mycol. 1986 Oct;24(5):407–413. doi: 10.1080/02681218680000621. [DOI] [PubMed] [Google Scholar]
  7. Hector R. F., Lyon F. L., Domer J. E. Immunological relatedness among Candida albicans and other pathogenic Candida species. Infect Immun. 1981 Dec;34(3):844–850. doi: 10.1128/iai.34.3.844-850.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hube B., Turver C. J., Odds F. C., Eiffert H., Boulnois G. J., Köchel H., Rüchel R. Sequence of the Candida albicans gene encoding the secretory aspartate proteinase. J Med Vet Mycol. 1991;29(2):129–132. [PubMed] [Google Scholar]
  9. Kobayashi I., Kondoh Y., Shimizu K., Tanaka K. A role of secreted proteinase of Candida albicans for the invasion of chick chorio-allantoic membrane. Microbiol Immunol. 1989;33(9):709–719. doi: 10.1111/j.1348-0421.1989.tb00958.x. [DOI] [PubMed] [Google Scholar]
  10. Kwon-Chung K. J., Lehman D., Good C., Magee P. T. Genetic evidence for role of extracellular proteinase in virulence of Candida albicans. Infect Immun. 1985 Sep;49(3):571–575. doi: 10.1128/iai.49.3.571-575.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Louie A., Dixon D. M., el-Maghrabi E. A., Burnett J. W., Baltch A. L., Smith R. P. Relationship between Candida albicans epidermolytic proteinase activity and virulence in mice. J Med Vet Mycol. 1994;32(1):59–64. [PubMed] [Google Scholar]
  12. Macdonald F., Odds F. C. Virulence for mice of a proteinase-secreting strain of Candida albicans and a proteinase-deficient mutant. J Gen Microbiol. 1983 Feb;129(2):431–438. doi: 10.1099/00221287-129-2-431. [DOI] [PubMed] [Google Scholar]
  13. Miyasaki S. H., White T. C., Agabian N. A fourth secreted aspartyl proteinase gene (SAP4) and a CARE2 repetitive element are located upstream of the SAP1 gene in Candida albicans. J Bacteriol. 1994 Mar;176(6):1702–1710. doi: 10.1128/jb.176.6.1702-1710.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Morrison C. J., Hurst S. F., Bragg S. L., Kuykendall R. J., Diaz H., Pohl J., Reiss E. Heterogeneity of the purified extracellular aspartyl proteinase from Candida albicans: characterization with monoclonal antibodies and N-terminal amino acid sequence analysis. Infect Immun. 1993 May;61(5):2030–2036. doi: 10.1128/iai.61.5.2030-2036.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ray T. L., Payne C. D. Comparative production and rapid purification of Candida acid proteinase from protein-supplemented cultures. Infect Immun. 1990 Feb;58(2):508–514. doi: 10.1128/iai.58.2.508-514.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ross I. K., De Bernardis F., Emerson G. W., Cassone A., Sullivan P. A. The secreted aspartate proteinase of Candida albicans: physiology of secretion and virulence of a proteinase-deficient mutant. J Gen Microbiol. 1990 Apr;136(4):687–694. doi: 10.1099/00221287-136-4-687. [DOI] [PubMed] [Google Scholar]
  17. Rüchel R. Properties of a purified proteinase from the yeast Candida albicans. Biochim Biophys Acta. 1981 May 14;659(1):99–113. doi: 10.1016/0005-2744(81)90274-6. [DOI] [PubMed] [Google Scholar]
  18. Rüchel R., Ritter B., Schaffrinski M. Modulation of experimental systemic murine candidosis by intravenous pepstatin. Zentralbl Bakteriol. 1990 Aug;273(3):391–403. doi: 10.1016/s0934-8840(11)80443-3. [DOI] [PubMed] [Google Scholar]
  19. Sobel J. D., Vazquez J. Candidemia and systemic candidiasis. Semin Respir Infect. 1990 Jun;5(2):123–137. [PubMed] [Google Scholar]
  20. Tamburini P. P., Dreyer R. N., Hansen J., Letsinger J., Elting J., Gore-Willse A., Dally R., Hanko R., Osterman D., Kamarck M. E. A fluorometric assay for HIV-protease activity using high-performance liquid chromatography. Anal Biochem. 1990 May 1;186(2):363–368. doi: 10.1016/0003-2697(90)90095-q. [DOI] [PubMed] [Google Scholar]
  21. Togni G., Sanglard D., Monod M. Acid proteinase secreted by Candida tropicalis: virulence in mice of a proteinase negative mutant. J Med Vet Mycol. 1994;32(4):257–265. doi: 10.1080/02681219480000331. [DOI] [PubMed] [Google Scholar]
  22. Tsuobi R., Kurita Y., Negi M., Ogawa H. A specific inhibitor of keratinolytic proteinase from Candida albicans could inhibit the cell growth of C. albicans. J Invest Dermatol. 1985 Nov;85(5):438–440. doi: 10.1111/1523-1747.ep12277147. [DOI] [PubMed] [Google Scholar]
  23. White T. C., Miyasaki S. H., Agabian N. Three distinct secreted aspartyl proteinases in Candida albicans. J Bacteriol. 1993 Oct;175(19):6126–6133. doi: 10.1128/jb.175.19.6126-6133.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Wright R. J., Carne A., Hieber A. D., Lamont I. L., Emerson G. W., Sullivan P. A. A second gene for a secreted aspartate proteinase in Candida albicans. J Bacteriol. 1992 Dec;174(23):7848–7853. doi: 10.1128/jb.174.23.7848-7853.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Zotter C., Haustein U. F., Schönborn C., Grimmecke H. D., Wand H. Die Wirkung von Pepstatin A auf die Candida-albicans-Infektion der Maus. Dermatol Monatsschr. 1990;176(2-3):189–198. [PubMed] [Google Scholar]
  26. el-Maghrabi E. A., Dixon D. M., Burnett J. W. Characterization of Candida albicans epidermolytic proteases and their role in yeast-cell adherence to keratinocytes. Clin Exp Dermatol. 1990 May;15(3):183–191. doi: 10.1111/j.1365-2230.1990.tb02069.x. [DOI] [PubMed] [Google Scholar]

Articles from Infection and Immunity are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES