1887

Abstract

The transition of from a yeast to a hyphal form is controlled by several transcriptional factors, including the key regulators Cph1 and Efg1, and is considered an important virulence attribute. These factors, especially Efg1, regulate the expression of hyphal-associated genes e.g. . In order to investigate the relevance of these transcriptional regulators for hyphal-independent genes, recently constructed and single mutants and a / double mutant lacking these factors were tested during interaction with oral epithelium and polymorphonuclear neutrophils. In contrast to the parental wild-type strain and the mutant, the and the / mutants did not produce hyphal forms in all experiments and were less capable of damaging epithelial cells and neutrophil granulocytes. The attenuated epithelial lesions of these mutants were correlated not only with reduced expression of the hyphal-associated gene , but also with the lack of and expression previously shown to be important for oral infections. An mutant strain carrying a plasmid-borne copy of the gene regained hyphal growth, damage of keratinocytes, granulocytes and the expression of and . Although and / mutants did not produce germ tubes during infection, expression of the hyphal-associated genes and was not completely abolished. A reduced capacity to stimulate an epithelial immune response manifested by a delayed onset of IL-1β, IL-8 and TNF expression was only observed in the /-infected tissue. These results provide further evidence for a combined regulation of different virulence factors, such as dimorphism and expression of genes. Furthermore, it could be demonstrated that the lack of Efg1 also caused reduced expression of hyphal-independent genes. Both the and the gene products are necessary for adequate induction of an immune response.

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2003-08-01
2024-04-20
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References

  1. Bockmuhl D. P, Ernst J. F. 2001; A potential phosphorylation site for an A-type kinase in the Efg1 regulator protein contributes to hyphal morphogenesis of Candida albicans . Genetics 157:1523–1530
    [Google Scholar]
  2. Borg-von Zepelin M, Beggah S, Boggian K, Sanglard D, Monod M. 1998; The expression of the secreted aspartyl proteinases Sap4 to Sap6 from Candida albicans in murine macrophages. Mol Microbiol 28:543–554 [CrossRef]
    [Google Scholar]
  3. Brown A. J, Gow N. A. 1999; Regulatory networks controlling Candida albicans morphogenesis. Trends Microbiol 7:333–338 [CrossRef]
    [Google Scholar]
  4. Calderone R. A, Fonzi W. A. 2001; Virulence factors of Candida albicans . Trends Microbiol 9:327–335 [CrossRef]
    [Google Scholar]
  5. Challacombe S. J. 1994; Immunologic aspects of oral candidiasis. Oral Surg Oral Med Oral Pathol 78:202–210 [CrossRef]
    [Google Scholar]
  6. Dieterich C, Schandar M, Noll M, Johannes F.-J, Brunner H, Graeve T, Rupp S. 2002; In vitro reconstructed human epithelia reveal contributions of Candida albicans EFG1 and CPH1 to adhesion and invasion. Microbiology 148:497–506
    [Google Scholar]
  7. Ernst J. F. 2000; Transcription factors in Candida albicans –environmental control of morphogenesis. Microbiology 146:1763–1774
    [Google Scholar]
  8. Eversole L. R, Reichart P. A, Ficarra G, Schmidt-Westhausen A, Romagnoli P, Pimpinelli N. 1997; Oral keratinocyte immune responses in HIV-associated candidiasis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 84:372–380 [CrossRef]
    [Google Scholar]
  9. Farah C. S, Elahi S, Pang G, Gotjamanos T, Seymour G. J, Clancy R. L, Ashman R. B. 2001; T cells augment monocyte and neutrophil function in host resistance against oropharyngeal candidiasis. Infect Immun 69:6110–6118 [CrossRef]
    [Google Scholar]
  10. Felk A, Kretschmar M, Albrecht A. 7 other authors 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 [CrossRef]
    [Google Scholar]
  11. Gillum A. M, Tsay E. Y, Kirsch D. R. 1984; Isolation of the Candida albicans gene for orotidine-5′-phosphate decarboxylase by complementation of S.cerevisiae ura3 and E. coli pyrF mutations. Mol Gen Genet 198:179–182 [CrossRef]
    [Google Scholar]
  12. Kohler J. R, Fink G. R. 1996; Candida albicans strains heterozygous and homozygous for mutations in mitogen-activated protein kinase signaling components have defects in hyphal development. Proc Natl Acad Sci U S A 93:13223–13228 [CrossRef]
    [Google Scholar]
  13. Lane S, Birse C, Zhou S, Matson R, Liu H. 2001; DNA array studies demonstrate convergent regulation of virulence factors by Cph1, Cph2, and Efg1 in Candida albicans . J Biol Chem 276:48988–48996 [CrossRef]
    [Google Scholar]
  14. Leberer E, Ziegelbauer K, Schmidt A, Harcus D, Dignard D, Ash J, Johnson L, Thomas D. Y. 1997; Virulence and hyphal formation of Candida albicans require the Ste20p-like protein kinase CaCla4p. Curr Biol 7:539–546 [CrossRef]
    [Google Scholar]
  15. Lewis R. E, Lo H. J, Raad I. I, Kontoyiannis D. P. 2002; Lack of catheter infection by the efg1 / efg1 cph1 / cph1 double-null mutant, a Candida albicans strain that is defective in filamentous growth. Antimicrob Agents Chemother 46:1153–1155 [CrossRef]
    [Google Scholar]
  16. Li J, Thornhill M. H. 2000; Growth-regulated peptide-alpha (GRO-alpha) production by oral keratinocytes: a comparison with skin keratinocytes. Cytokine 12:1409–1413 [CrossRef]
    [Google Scholar]
  17. Li J, Farthing P. M, Thornhill M. H. 2000; Oral and skin keratinocytes are stimulated to secrete monocyte chemoattractant protein-1 by tumour necrosis factor-alpha and interferon-gamma. J Oral Pathol Med 29:438–444 [CrossRef]
    [Google Scholar]
  18. Lo H. J, Kohler J. R, DiDomenico B, Loebenberg D, Cacciapuoti A, Fink G. R. 1997; Nonfilamentous C.albicans mutants are avirulent. Cell 90:939–949 [CrossRef]
    [Google Scholar]
  19. Maneu V, Cervera A. M, Martinez J. P, Gozalbo D. 1996; Molecular cloning and characterization of a Candida albicans gene (EFB1) coding for the elongation factor EF-1 beta. FEMS Microbiol Lett 145:157–162
    [Google Scholar]
  20. 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
    [Google Scholar]
  21. Phan Q. T, Belanger P. H, Filler S. G. 2000; Role of hyphal formation in interactions of Candida albicans with endothelial cells. Infect Immun 68:3485–3490 [CrossRef]
    [Google Scholar]
  22. Riggle P. J, Andrutis K. A, Chen X, Tzipori S. R, Kumamoto C. A. 1999; Invasive lesions containing filamentous forms produced by a Candida albicans mutant that is defective in filamentous growth in culture. Infect Immun 67:3649–3652
    [Google Scholar]
  23. Schaller M, Schafer W, Korting H. C, Hube B. 1998; Differential expression of secreted aspartyl proteinases in a model of human oral candidosis and in patient samples from the oral cavity. Mol Microbiol 29:605–615 [CrossRef]
    [Google Scholar]
  24. Schaller M, Korting H. C, Schafer W, Bastert J, Chen W, Hube B. 1999; Secreted aspartic proteinase (Sap) activity contributes to tissue damage in a model of human oral candidosis. Mol Microbiol 34:169–180 [CrossRef]
    [Google Scholar]
  25. Schaller M, Mailhammer R, Grassl G, Sander C. A, Hube B, Korting H. C. 2002; Infection of human oral epithelia with Candida species induces cytokine expression correlated to the degree of virulence. J Invest Dermatol 118:652–657 [CrossRef]
    [Google Scholar]
  26. Schröppel K, Sprosser K, Whiteway M, Thomas D. Y, Rollinghoff M, Csank C. 2000; Repression of hyphal proteinase expression by the mitogen-activated protein (MAP) kinase phosphatase Cpp1p of Candida albicans is independent of the MAP kinase Cek1p. Infect Immun 68:7159–7161 [CrossRef]
    [Google Scholar]
  27. Schweizer A, Rupp S, Taylor B. N, Rollinghoff M, Schröppel K. 2000; The TEA/ATTS transcription factor CaTec1p regulates hyphal development and virulence in Candida albicans . Mol Microbiol 38:435–445 [CrossRef]
    [Google Scholar]
  28. Sonneborn A, Bockmuhl D. P, Ernst J. F. 1999a; Chlamydospore formation in Candida albicans requires the Efg1p morphogenetic regulator. Infect Immun 67:5514–5517
    [Google Scholar]
  29. Sonneborn A, Tebarth B, Ernst J. F. 1999b; Control of white-opaque phenotypic switching in Candida albicans by the Efg1p morphogenetic regulator. Infect Immun 67:4655–4660
    [Google Scholar]
  30. Srikantha T, Tsai L. K, Daniels K, Soll D. R. 2000; EFG1 null mutants of Candida albicans switch but cannot express the complete phenotype of white-phase budding cells. J Bacteriol 182:1580–1591 [CrossRef]
    [Google Scholar]
  31. 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 [CrossRef]
    [Google Scholar]
  32. Stoldt V. R, Sonneborn A, Leuker C. E, Ernst J. F. 1997; Efg1p, an essential regulator of morphogenesis of the human pathogen Candida albicans , is a member of a conserved class of bHLH proteins regulating morphogenetic processes in fungi. EMBO J 16:1982–1991 [CrossRef]
    [Google Scholar]
  33. Uehara A, Sugawara S, Tamai R, Takada H. 2001; Contrasting responses of human gingival and colonic epithelial cells to lipopolysaccharides, lipoteichoic acids and peptidoglycans in the presence of soluble CD14. Med Microbiol Immunol 189:185–192 [CrossRef]
    [Google Scholar]
  34. Vazquez-Torres A, Balish E. 1997; Macrophages in resistance to candidiasis. Microbiol Mol Biol Rev 61:170–192
    [Google Scholar]
  35. Weide M. R, Ernst J. F. 1999; Caco-2 monolayer as a model for transepithelial migration of the fungal pathogen Candida albicans . Mycoses 42:61–67 [CrossRef]
    [Google Scholar]
  36. Wróblewski F, John S. L. 1955; Lactic dehydrogenase activity in blood. Proc Soc Exp Biol Med 90:210–213 [CrossRef]
    [Google Scholar]
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