This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hube, B. Articles by Gow, N. A. Search for Related Content PubMed PubMed Citation Articles by Hube, B. Articles by Gow, N. A.

 Previous Article  |  Next Article 

Infect. Immun., 09 1997, 3529-3538, Vol 65, No. 9
Copyright © 1997, American Society for Microbiology

Disruption of each of the secreted aspartyl proteinase genes SAP1, SAP2, and SAP3 of Candida albicans attenuates virulence

B Hube, D Sanglard, FC Odds, D Hess, M Monod, W Schafer, AJ Brown and NA Gow
Department of Molecular and Cell Biology, Institute of Medical Science, University of Aberdeen, Scotland. hube@botanik.uni-hamburg.de

Secreted aspartyl proteinases (Saps), encoded by a gene family with at least nine members (SAP1 to SAP9), are one of the most discussed virulence factors produced by the human pathogen Candida albicans. In order to study the role of each Sap isoenzyme in pathogenicity, we have constructed strains which harbor mutations at selected SAP genes. SAP1, SAP2, and SAP3, which are regulated differentially in vitro, were mutated by targeted gene disruption. The growth rates of all homozygous null mutants were similar to those of the isogenic wild-type parental strain (SC5314) in complex and defined media. In medium with protein as the sole source of nitrogen, sap1 and sap3 mutants grew with reduced growth rates but reached optical densities similar to those measured for SC5314. In contrast, sap2 null mutants tended to clump, grew poorly in this medium, and produced the lowest proteolytic activity. Addition of ammonium ions reversed such growth defects. These results support the view that Sap2 is the dominant isoenzyme. When sap1, sap2, and sap3 mutants were injected intravenously in guinea pigs and mice, the animals had increased survival rates compared to those of control animals infected with SC5314. However, reduction of proteolytic activity in vitro did not correlate directly with the extent of attenuation of virulence observed for all Sap-deficient mutants. These data suggest that SAP1, SAP2, and SAP3 all contribute to the overall virulence of C. albicans and presumably all play important roles during disseminated infections.

This article has been cited by other articles:

• Chaffin, W. L. (2008). Candida albicans Cell Wall Proteins. Microbiol. Mol. Biol. Rev. 72: 495-544 [Abstract] [Full Text]  
• Kleemann, J., Takahara, H., Stuber, K., O'Connell, R. (2008). Identification of soluble secreted proteins from appressoria of Colletotrichum higginsianum by analysis of expressed sequence tags. Microbiology 154: 1204-1217 [Abstract] [Full Text]  
• Fu, Y., Luo, G., Spellberg, B. J., Edwards, J. E. Jr., Ibrahim, A. S. (2008). Gene Overexpression/Suppression Analysis of Candidate Virulence Factors of Candida albicans. Eukaryot Cell 7: 483-492 [Abstract] [Full Text]  
• Staib, P., Lermann, U., Bla -Warmuth, J., Degel, B., Wurzner, R., Monod, M., Schirmeister, T., Morschhauser, J. (2008). Tetracycline-Inducible Expression of Individual Secreted Aspartic Proteases in Candida albicans Allows Isoenzyme-Specific Inhibitor Screening. Antimicrob. Agents Chemother. 52: 146-156 [Abstract] [Full Text]  
• Jackson, B. E., Wilhelmus, K. R., Hube, B. (2007). The Role of Secreted Aspartyl Proteinases in Candida albicans Keratitis. IOVS 48: 3559-3565 [Abstract] [Full Text]  
• Biswas, S., Van Dijck, P., Datta, A. (2007). Environmental Sensing and Signal Transduction Pathways Regulating Morphopathogenic Determinants of Candida albicans. Microbiol. Mol. Biol. Rev. 71: 348-376 [Abstract] [Full Text]  
• Schaefer, D., Cote, P., Whiteway, M., Bennett, R. J. (2007). Barrier Activity in Candida albicans Mediates Pheromone Degradation and Promotes Mating. Eukaryot Cell 6: 907-918 [Abstract] [Full Text]  
• Martinez, P., Ljungdahl, P. O. (2005). Divergence of Stp1 and Stp2 Transcription Factors in Candida albicans Places Virulence Factors Required for Proper Nutrient Acquisition under Amino Acid Control. Mol. Cell. Biol. 25: 9435-9446 [Abstract] [Full Text]  
• Taylor, B. N., Hannemann, H., Sehnal, M., Biesemeier, A., Schweizer, A., Rollinghoff, M., Schroppel, K. (2005). Induction of SAP7 Correlates with Virulence in an Intravenous Infection Model of Candidiasis but Not in a Vaginal Infection Model in Mice. Infect. Immun. 73: 7061-7063 [Abstract] [Full Text]  
• Schaller, M., Korting, H. C., Borelli, C., Hamm, G., Hube, B. (2005). Candida albicans-Secreted Aspartic Proteinases Modify the Epithelial Cytokine Response in an In Vitro Model of Vaginal Candidiasis. Infect. Immun. 73: 2758-2765 [Abstract] [Full Text]  
• Copping, V. M. S., Barelle, C. J., Hube, B., Gow, N. A. R., Brown, A. J. P., Odds, F. C. (2005). Exposure of Candida albicans to antifungal agents affects expression of SAP2 and SAP9 secreted proteinase genes. J Antimicrob Chemother 55: 645-654 [Abstract] [Full Text]  
• Tavanti, A., Pardini, G., Campa, D., Davini, P., Lupetti, A., Senesi, S. (2004). Differential Expression of Secretory Aspartyl Proteinase Genes (SAP1-10) in Oral Candida albicans Isolates with Distinct Karyotypes. J. Clin. Microbiol. 42: 4726-4734 [Abstract] [Full Text]  
• Brand, A., MacCallum, D. M., Brown, A. J. P., Gow, N. A. R., Odds, F. C. (2004). Ectopic Expression of URA3 Can Influence the Virulence Phenotypes and Proteome of Candida albicans but Can Be Overcome by Targeted Reintegration of URA3 at the RPS10 Locus. Eukaryot Cell 3: 900-909 [Abstract] [Full Text]  
• Hoffman, B., Breuil, C. (2004). Disruption of the Subtilase Gene, albin1, in Ophiostoma piliferum. Appl. Environ. Microbiol. 70: 3898-3903 [Abstract] [Full Text]  
• Sanchez, A. A., Johnston, D. A., Myers, C., Edwards, J. E. Jr., Mitchell, A. P., Filler, S. G. (2004). Relationship between Candida albicans Virulence during Experimental Hematogenously Disseminated Infection and Endothelial Cell Damage In Vitro. Infect. Immun. 72: 598-601 [Abstract] [Full Text]  
• Panwar, S. L., Legrand, M., Dignard, D., Whiteway, M., Magee, Paul. T. (2003). MF{alpha}1, the Gene Encoding the {alpha} Mating Pheromone of Candida albicans. Eukaryot Cell 2: 1350-1360 [Abstract] [Full Text]  
• Borst, A., Fluit, A. C. (2003). High levels of hydrolytic enzymes secreted by Candida albicans isolates involved in respiratory infections. J Med Microbiol 52: 971-974 [Abstract] [Full Text]  
• Morrison, C. J., Hurst, S. F., Reiss, E. (2003). Competitive Binding Inhibition Enzyme-Linked Immunosorbent Assay That Uses the Secreted Aspartyl Proteinase of Candida albicans as an Antigenic Marker for Diagnosis of Disseminated Candidiasis. CVI 10: 835-848 [Abstract] [Full Text]  
• Naglik, J. R., Challacombe, S. J., Hube, B. (2003). Candida albicans Secreted Aspartyl Proteinases in Virulence and Pathogenesis. Microbiol. Mol. Biol. Rev. 67: 400-428 [Abstract] [Full Text]  
• Jong, A. Y., Chen, S. H. M., Stins, M. F., Kim, K. S., Tuan, T.-L., Huang, S.-H. (2003). Binding of Candida albicans enolase to plasmin(ogen) results in enhanced invasion of human brain microvascular endothelial cells. J Med Microbiol 52: 615-622 [Abstract] [Full Text]  
• Schaller, M., Bein, M., Korting, H. C., Baur, S., Hamm, G., Monod, M., Beinhauer, S., Hube, B. (2003). The Secreted Aspartyl Proteinases Sap1 and Sap2 Cause Tissue Damage in an In Vitro Model of Vaginal Candidiasis Based on Reconstituted Human Vaginal Epithelium. Infect. Immun. 71: 3227-3234 [Abstract] [Full Text]  
• Blankenship, J. R., Wormley, F. L., Boyce, M. K., Schell, W. A., Filler, S. G., Perfect, J. R., Heitman, J. (2003). Calcineurin Is Essential for Candida albicans Survival in Serum and Virulence. Eukaryot Cell 2: 422-430 [Abstract] [Full Text]  
• Chen, Y.-C., Wu, C.-C., Chung, W.-L., Lee, F.-J. S. (2002). Differential secretion of Sap4-6 proteins in Candida albicans during hyphae formation. Microbiology 148: 3743-3754 [Abstract] [Full Text]  
• Felk, A., Kretschmar, M., Albrecht, A., Schaller, M., Beinhauer, S., Nichterlein, T., Sanglard, D., Korting, H. C., Schafer, W., Hube, B. (2002). Candida albicans Hyphal Formation and the Expression of the Efg1-Regulated Proteinases Sap4 to Sap6 Are Required for the Invasion of Parenchymal Organs. Infect. Immun. 70: 3689-3700 [Abstract] [Full Text]  
• Van Dijck, P., De Rop, L., Szlufcik, K., Van Ael, E., Thevelein, J. M. (2002). Disruption of the Candida albicans TPS2 Gene Encoding Trehalose-6-Phosphate Phosphatase Decreases Infectivity without Affecting Hypha Formation. Infect. Immun. 70: 1772-1782 [Abstract] [Full Text]  
• Staib, P., Kretschmar, M., Nichterlein, T., Hof, H., Morschhauser, J. (2002). Transcriptional Regulators Cph1p and Efg1p Mediate Activation of the Candida albicans Virulence Gene SAP5 during Infection. Infect. Immun. 70: 921-927 [Abstract] [Full Text]  
• Hube, B., Naglik, J. (2001). Candida albicans proteinases: resolving the mystery of a gene family. Microbiology 147: 1997-2005 [Full Text]  
• SCHALLER, M., JANUSCHKE, E., SCHACKERT, C., WOERLE, B., KORTING, H. C. (2001). Different isoforms of secreted aspartyl proteinases (Sap) are expressed by Candida albicans during oral and cutaneous candidosis in vivo. J Med Microbiol 50: 743-747 [Abstract] [Full Text]  
• Lee, S. A., Mao, Y., Zhang, Z., Wong, B. (2001). Overexpression of a dominant-negative allele of YPT1 inhibits growth and aspartyl protease secretion in Candida albicans. Microbiology 147: 1961-1970 [Abstract] [Full Text]  
• Strauß, A., Michel, S., Morschhäuser, J. (2001). Analysis of Phase-Specific Gene Expression at the Single-Cell Level in the White-Opaque Switching System of Candida albicans. J. Bacteriol. 183: 3761-3769 [Abstract] [Full Text]  
• Hube, B., Hess, D., Baker, C. A., Schaller, M., Schäfer, W., Dolan, J. W. (2001). The role and relevance of phospholipase D1 during growth and dimorphism of Candida albicans. Microbiology 147: 879-889 [Abstract] [Full Text]  
• Weber, Y., Santore, U. J., Ernst, J. F., Swoboda, R. K. (2001). Divergence of Eukaryotic Secretory Components: the Candida albicans Homolog of the Saccharomyces cerevisiae Sec20 Protein Is N Terminally Truncated, and Its Levels Determine Antifungal Drug Resistance and Growth. J. Bacteriol. 183: 46-54 [Abstract] [Full Text]  
• Davis, D., Edwards, J. E. Jr., Mitchell, A. P., Ibrahim, A. S. (2000). Candida albicans RIM101 pH Response Pathway Is Required for Host-Pathogen Interactions. Infect. Immun. 68: 5953-5959 [Abstract] [Full Text]  
• Odds, F. C., Van Nuffel, L., Gow, N. A. R. (2000). Survival in experimental Candida albicans infections depends on inoculum growth conditions as well as animal host. Microbiology 146: 1881-1889 [Abstract] [Full Text]  
• RUMA-HAYNES, P., BROWNLEE, A. G., SORRELL, T. C. (2000). A rapid method for detecting extracellular proteinase activity in Cryptococcus neoformans and a survey of 63 isolates. J Med Microbiol 49: 733-737 [Abstract] [Full Text]  
• Wu, T., Wright, K., Hurst, S. F., Morrison, C. J. (2000). Enhanced Extracellular Production of Aspartyl Proteinase, a Virulence Factor, by Candida albicans Isolates following Growth in Subinhibitory Concentrations of Fluconazole. Antimicrob. Agents Chemother. 44: 1200-1208 [Abstract] [Full Text]  
• Tsuchimori, N., Sharkey, L. L., Fonzi, W. A., French, S. W., Edwards, J. E. Jr., Filler, S. G. (2000). Reduced Virulence of HWP1-Deficient Mutants of Candida albicans and Their Interactions with Host Cells. Infect. Immun. 68: 1997-2002 [Abstract] [Full Text]  
• Hammacott, J. E., Williams, P. H., Cashmore, A. M. (2000). Candida albicans CFL1 encodes a functional ferric reductase activity that can rescue a Saccharomyces cerevisiae fre1 mutant. Microbiology 146: 869-876 [Abstract] [Full Text]  
• O’Day, D. M., Head, W. S., Csank, C., Shetlar, D. J., Robinson, R. D., McCollum, G. W., Yang, R., Zhu, T. L., Wang, M. X. (2000). Differences in Virulence between Two Candida albicans Strains in Experimental Keratitis. IOVS 41: 1116-1121 [Abstract] [Full Text]  
• Ghannoum, M. A. (2000). Potential Role of Phospholipases in Virulence and Fungal Pathogenesis. Clin. Microbiol. Rev. 13: 122-143 [Abstract] [Full Text]  
• Kretschmar, M., Hube, B., Bertsch, T., Sanglard, D., Merker, R., Schroder, M., Hof, H., Nichterlein, T. (1999). Germ Tubes and Proteinase Activity Contribute to Virulence of Candida albicans in Murine Peritonitis. Infect. Immun. 67: 6637-6642 [Abstract] [Full Text]  
• Kvaal, C., Lachke, S. A., Srikantha, T., Daniels, K., McCoy, J., Soll, D. R. (1999). Misexpression of the Opaque-Phase-Specific Gene PEP1 (SAP1) in the White Phase of Candida albicans Confers Increased Virulence in a Mouse Model of Cutaneous Infection. Infect. Immun. 67: 6652-6662 [Abstract] [Full Text]  
• Mao, Y., Kalb, V. F., Wong, B. (1999). Overexpression of a Dominant-Negative Allele of SEC4 Inhibits Growth and Protein Secretion in Candida albicans. J. Bacteriol. 181: 7235-7242 [Abstract] [Full Text]  
• Korting, H. C., Schaller, M., Eder, G., Hamm, G., Böhmer, U., Hube, B. (1999). Effects of the Human Immunodeficiency Virus (HIV) Proteinase Inhibitors Saquinavir and Indinavir on In Vitro Activities of Secreted Aspartyl Proteinases of Candida albicans Isolates from HIV-Infected Patients. Antimicrob. Agents Chemother. 43: 2038-2042 [Abstract] [Full Text]  
• Rieg, G., Fu, Y., Ibrahim, A. S., Zhou, X., Filler, S. G., Edwards, J. E. Jr. (1999). Unanticipated Heterogeneity in Growth Rate and Virulence among Candida albicans AAF1 Null Mutants. Infect. Immun. 67: 3193-3198 [Abstract] [Full Text]  
• Naglik, J. R., Newport, G., White, T. C., Fernandes-Naglik, L. L., Greenspan, J. S., Greenspan, D., Sweet, S. P., Challacombe, S. J., Agabian, N. (1999). In Vivo Analysis of Secreted Aspartyl Proteinase Expression in Human Oral Candidiasis. Infect. Immun. 67: 2482-2490 [Abstract] [Full Text]  
• Leidich, S. D., Ibrahim, A. S., Fu, Y., Koul, A., Jessup, C., Vitullo, J., Fonzi, W., Mirbod, F., Nakashima, S., Nozawa, Y., Ghannoum, M. A. (1998). Cloning and Disruption of caPLB1, a Phospholipase B Gene Involved in the Pathogenicity of Candida albicans. J. Biol. Chem. 273: 26078-26086 [Abstract] [Full Text]  
• Csank, C., Schroppel, K., Leberer, E., Harcus, D., Mohamed, O., Meloche, S., Thomas, D. Y., Whiteway, M. (1998). Roles of the Candida albicans Mitogen-Activated Protein Kinase Homolog, Cek1p, in Hyphal Development and Systemic Candidiasis. Infect. Immun. 66: 2713-2721 [Abstract] [Full Text]  
• Ibrahim, A. S., Filler, S. G., Sanglard, D., Edwards, J. E. Jr., Hube, B. (1998). Secreted Aspartyl Proteinases and Interactions of Candida albicans with Human Endothelial Cells. Infect. Immun. 66: 3003-3005 [Abstract] [Full Text]  
• Chaffin, W. L., Lopez-Ribot, J. L., Casanova, M., Gozalbo, D., Martinez, J. P. (1998). Cell Wall and Secreted Proteins of Candida albicans: Identification, Function, and Expression. Microbiol. Mol. Biol. Rev. 62: 130-180 [Abstract] [Full Text]