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. 1996 Feb;64(2):466–471. doi: 10.1128/iai.64.2.466-471.1996

Elevated aspartic proteinase secretion and experimental pathogenicity of Candida albicans isolates from oral cavities of subjects infected with human immunodeficiency virus.

F De Bernardis 1, P Chiani 1, M Ciccozzi 1, G Pellegrini 1, T Ceddia 1, G D'Offizzi 1, I Quinti 1, P A Sullivan 1, A Cassone 1
PMCID: PMC173787  PMID: 8550193

Abstract

Isolates of Candida albicans from the oral cavities of subjects at different stages of human immunodeficiency virus (HIV) infection or uninfected controls were examined for (i) production of aspartic proteinase(s), a putative virulence-associated factor(s); (ii) the presence in the fungal genome of two major genes (SAP1 and SAP2) of the aspartic proteinase family; and (iii) experimental pathogenicity in a murine model of systemic infection. It was found that the fungal isolates from symptomatic patients secreted, on average, up to eightfold more proteinase than the isolates from uninfected or HIV-infected but asymptomatic subjects. This differential property was stably expressed by the strains even after years of maintenance in stock cultures. Moreover, representative high-proteinase isolates were significantly more pathogenic for mice than low-proteinase isolates of C. albicans. The characters high proteinase and increased virulence were not associated with a single molecular type or category identifiable through DNA fingerprinting or pulsed-field electrophoretic karyotype, and both SAP1 and SAP2 genes were present in both categories of isolates, on the same respective chromosomes. In conclusion, our data suggest that during HIV infection more-virulent strains or biotypes of C. albicans which are identifiable by direct analysis of virulence determinants are selected. It also appears that the biotype switch to increased aspartic proteinase and virulence properties occurs before the HIV-infected subject enters the symptomatic stage and overt AIDS.

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Selected References

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  1. Agresti M. G., de Bernardis F., Mondello F., Bellocco R., Carosi G. P., Caputo R. M., Milazzo F., Chiodo F., Giannini V., Minoli L. Clinical and mycological evaluation of fluconazole in the secondary prophylaxis of esophageal candidiasis in AIDS patients. An open, multicenter study. Eur J Epidemiol. 1994 Feb;10(1):17–22. doi: 10.1007/BF01717446. [DOI] [PubMed] [Google Scholar]
  2. Barchiesi F., Colombo A. L., McGough D. A., Fothergill A. W., Rinaldi M. G. In vitro activity of itraconazole against fluconazole-susceptible and -resistant Candida albicans isolates from oral cavities of patients infected with human immunodeficiency virus. Antimicrob Agents Chemother. 1994 Jul;38(7):1530–1533. doi: 10.1128/aac.38.7.1530. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Boerlin P., Boerlin-Petzold F., Durussel C., Addo M., Pagani J. L., Chave J. P., Bille J. Cluster of oral atypical Candida albicans isolates in a group of human immunodeficiency virus-positive drug users. J Clin Microbiol. 1995 May;33(5):1129–1135. doi: 10.1128/jcm.33.5.1129-1135.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brawner D. L., Cutler J. E. Oral Candida albicans isolates from nonhospitalized normal carriers, immunocompetent hospitalized patients, and immunocompromised patients with or without acquired immunodeficiency syndrome. J Clin Microbiol. 1989 Jun;27(6):1335–1341. doi: 10.1128/jcm.27.6.1335-1341.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bruatto M., Vidotto V., Marinuzzi G., Raiteri R., Sinicco A. Candida albicans biotypes in human immunodeficiency virus type 1-infected patients with oral candidiasis before and after antifungal therapy. J Clin Microbiol. 1991 Apr;29(4):726–730. doi: 10.1128/jcm.29.4.726-730.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cantorna M. T., Balish E. Role of CD4+ lymphocytes in resistance to mucosal candidiasis. Infect Immun. 1991 Jul;59(7):2447–2455. doi: 10.1128/iai.59.7.2447-2455.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Carruba G., Pontieri E., De Bernardis F., Martino P., Cassone A. DNA fingerprinting and electrophoretic karyotype of environmental and clinical isolates of Candida parapsilosis. J Clin Microbiol. 1991 May;29(5):916–922. doi: 10.1128/jcm.29.5.916-922.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cassone A., Boccanera M., Adriani D., Santoni G., De Bernardis F. Rats clearing a vaginal infection by Candida albicans acquire specific, antibody-mediated resistance to vaginal reinfection. Infect Immun. 1995 Jul;63(7):2619–2624. doi: 10.1128/iai.63.7.2619-2624.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cutler J. E. Putative virulence factors of Candida albicans. Annu Rev Microbiol. 1991;45:187–218. doi: 10.1146/annurev.mi.45.100191.001155. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. De Bernardis F., Boccanera M., Rainaldi L., Guerra C. E., Quinti I., Cassone A. The secretion of aspartyl proteinase, a virulence enzyme, by isolates of Candida albicans from the oral cavity of HIV-infected subjects. Eur J Epidemiol. 1992 May;8(3):362–367. doi: 10.1007/BF00158569. [DOI] [PubMed] [Google Scholar]
  12. De Bernardis F., Cassone A., Sturtevant J., Calderone R. Expression of Candida albicans SAP1 and SAP2 in experimental vaginitis. Infect Immun. 1995 May;63(5):1887–1892. doi: 10.1128/iai.63.5.1887-1892.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fauci A. S. The human immunodeficiency virus: infectivity and mechanisms of pathogenesis. Science. 1988 Feb 5;239(4840):617–622. doi: 10.1126/science.3277274. [DOI] [PubMed] [Google Scholar]
  14. Fox R., Neal K. R., Leen C. L., Ellis M. E., Mandal B. K. Fluconazole resistant candida in AIDS. J Infect. 1991 Mar;22(2):201–204. doi: 10.1016/0163-4453(91)91767-r. [DOI] [PubMed] [Google Scholar]
  15. Holmberg K., Meyer R. D. Fungal infections in patients with AIDS and AIDS-related complex. Scand J Infect Dis. 1986;18(3):179–192. doi: 10.3109/00365548609032326. [DOI] [PubMed] [Google Scholar]
  16. Hube B., Monod M., Schofield D. A., Brown A. J., Gow N. A. Expression of seven members of the gene family encoding secretory aspartyl proteinases in Candida albicans. Mol Microbiol. 1994 Oct;14(1):87–99. doi: 10.1111/j.1365-2958.1994.tb01269.x. [DOI] [PubMed] [Google Scholar]
  17. Imam N., Carpenter C. C., Mayer K. H., Fisher A., Stein M., Danforth S. B. Hierarchical pattern of mucosal candida infections in HIV-seropositive women. Am J Med. 1990 Aug;89(2):142–146. doi: 10.1016/0002-9343(90)90291-k. [DOI] [PubMed] [Google Scholar]
  18. Kaminishi H., Miyaguchi H., Tamaki T., Suenaga N., Hisamatsu M., Mihashi I., Matsumoto H., Maeda H., Hagihara Y. Degradation of humoral host defense by Candida albicans proteinase. Infect Immun. 1995 Mar;63(3):984–988. doi: 10.1128/iai.63.3.984-988.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Klein R. S., Harris C. A., Small C. B., Moll B., Lesser M., Friedland G. H. Oral candidiasis in high-risk patients as the initial manifestation of the acquired immunodeficiency syndrome. N Engl J Med. 1984 Aug 9;311(6):354–358. doi: 10.1056/NEJM198408093110602. [DOI] [PubMed] [Google Scholar]
  20. Lupetti A., Guzzi G., Paladini A., Swart K., Campa M., Senesi S. Molecular typing of Candida albicans in oral candidiasis: karyotype epidemiology with human immunodeficiency virus-seropositive patients in comparison with that with healthy carriers. J Clin Microbiol. 1995 May;33(5):1238–1242. doi: 10.1128/jcm.33.5.1238-1242.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. 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]
  22. Magee B. B., Hube B., Wright R. J., Sullivan P. J., Magee P. T. The genes encoding the secreted aspartyl proteinases of Candida albicans constitute a family with at least three members. Infect Immun. 1993 Aug;61(8):3240–3243. doi: 10.1128/iai.61.8.3240-3243.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Magee B. B., Koltin Y., Gorman J. A., Magee P. T. Assignment of cloned genes to the seven electrophoretically separated Candida albicans chromosomes. Mol Cell Biol. 1988 Nov;8(11):4721–4726. doi: 10.1128/mcb.8.11.4721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Magee P. T., Bowdin L., Staudinger J. Comparison of molecular typing methods for Candida albicans. J Clin Microbiol. 1992 Oct;30(10):2674–2679. doi: 10.1128/jcm.30.10.2674-2679.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. McCullough M., Ross B., Reade P. Characterization of genetically distinct subgroup of Candida albicans strains isolated from oral cavities of patients infected with human immunodeficiency virus. J Clin Microbiol. 1995 Mar;33(3):696–700. doi: 10.1128/jcm.33.3.696-700.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Mencacci A., Torosantucci A., Spaccapelo R., Romani L., Bistoni F., Cassone A. A mannoprotein constituent of Candida albicans that elicits different levels of delayed-type hypersensitivity, cytokine production, and anticandidal protection in mice. Infect Immun. 1994 Dec;62(12):5353–5360. doi: 10.1128/iai.62.12.5353-5360.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Merz W. G., Connelly C., Hieter P. Variation of electrophoretic karyotypes among clinical isolates of Candida albicans. J Clin Microbiol. 1988 May;26(5):842–845. doi: 10.1128/jcm.26.5.842-845.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Monod M., Togni G., Hube B., Sanglard D. Multiplicity of genes encoding secreted aspartic proteinases in Candida species. Mol Microbiol. 1994 Jul;13(2):357–368. doi: 10.1111/j.1365-2958.1994.tb00429.x. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Pfaller M. A., Rhine-Chalberg J., Redding S. W., Smith J., Farinacci G., Fothergill A. W., Rinaldi M. G. Variations in fluconazole susceptibility and electrophoretic karyotype among oral isolates of Candida albicans from patients with AIDS and oral candidiasis. J Clin Microbiol. 1994 Jan;32(1):59–64. doi: 10.1128/jcm.32.1.59-64.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Quinti I., Palma C., Guerra E. C., Gomez M. J., Mezzaroma I., Aiuti F., Cassone A. Proliferative and cytotoxic responses to mannoproteins of Candida albicans by peripheral blood lymphocytes of HIV-infected subjects. Clin Exp Immunol. 1991 Sep;85(3):485–492. doi: 10.1111/j.1365-2249.1991.tb05754.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Romani L., Mocci S., Bietta C., Lanfaloni L., Puccetti P., Bistoni F. Th1 and Th2 cytokine secretion patterns in murine candidiasis: association of Th1 responses with acquired resistance. Infect Immun. 1991 Dec;59(12):4647–4654. doi: 10.1128/iai.59.12.4647-4654.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. 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]
  34. Schmid J., Odds F. C., Wiselka M. J., Nicholson K. G., Soll D. R. Genetic similarity and maintenance of Candida albicans strains from a group of AIDS patients, demonstrated by DNA fingerprinting. J Clin Microbiol. 1992 Apr;30(4):935–941. doi: 10.1128/jcm.30.4.935-941.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Soll D. R. High-frequency switching in Candida albicans. Clin Microbiol Rev. 1992 Apr;5(2):183–203. doi: 10.1128/cmr.5.2.183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Sullivan D., Bennett D., Henman M., Harwood P., Flint S., Mulcahy F., Shanley D., Coleman D. Oligonucleotide fingerprinting of isolates of Candida species other than C. albicans and of atypical Candida species from human immunodeficiency virus-positive and AIDS patients. J Clin Microbiol. 1993 Aug;31(8):2124–2133. doi: 10.1128/jcm.31.8.2124-2133.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Torosantucci A., Bromuro C., Gomez M. J., Ausiello C. M., Urbani F., Cassone A. Identification of a 65-kDa mannoprotein as a main target of human cell-mediated immune response to Candida albicans. J Infect Dis. 1993 Aug;168(2):427–435. doi: 10.1093/infdis/168.2.427. [DOI] [PubMed] [Google Scholar]
  38. Vazquez J. A., Beckley A., Sobel J. D., Zervos M. J. Comparison of restriction enzyme analysis and pulsed-field gradient gel electrophoresis as typing systems for Candida albicans. J Clin Microbiol. 1991 May;29(5):962–967. doi: 10.1128/jcm.29.5.962-967.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Vollrath D., Davis R. W. Resolution of DNA molecules greater than 5 megabases by contour-clamped homogeneous electric fields. Nucleic Acids Res. 1987 Oct 12;15(19):7865–7876. doi: 10.1093/nar/15.19.7865. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Whelan W. L., Kirsch D. R., Kwon-Chung K. J., Wahl S. M., Smith P. D. Candida albicans in patients with the acquired immunodeficiency syndrome: absence of a novel of hypervirulent strain. J Infect Dis. 1990 Aug;162(2):513–518. doi: 10.1093/infdis/162.2.513. [DOI] [PubMed] [Google Scholar]

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