1887

Abstract

In , the gene, encoding a cell wall-associated acid trehalase, has been considered as a potentially interesting target in the search for new antifungal compounds. A phenotypic characterization of the double disruptant Δ/Δ mutant showed that it was unable to grow on exogenous trehalose as sole carbon source. Unlike actively growing cells from the parental strain (CAI4), the Δ null mutant displayed higher resistance to environmental insults, such as heat shock (42 °C) or saline exposure (0.5 M NaCl), and to both mild and severe oxidative stress (5 and 50 mM HO), which are relevant during infections. Parallel measurements of intracellular trehalose and trehalose-metabolizing enzymes revealed that significant amounts of the disaccharide were stored in response to thermal and oxidative challenge in the two cell types. The antioxidant activities of catalase and glutathione reductase were triggered by moderate oxidative exposure (5 mM HO), whereas superoxide dismutase was inhibited dramatically by HO, where a more marked decrease was observed in Δ cells. In turn, the Δ mutant exhibited a decreased capacity of hypha and pseudohypha formation tested in different media. Finally, the homozygous null mutant in a mouse model of systemic candidiasis displayed strongly reduced pathogenicity compared with parental or heterozygous strains. These results suggest not only a novel role for the gene in dimorphism and infectivity, but also that an interconnection between stress resistance, dimorphic conversion and virulence in may be reconsidered. They also support the hypothesis that Atc1p is not involved in the physiological hydrolysis of endogenous trehalose.

Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.2006/003921-0
2007-05-01
2019-10-22
Loading full text...

Full text loading...

/deliver/fulltext/micro/153/5/1372.html?itemId=/content/journal/micro/10.1099/mic.0.2006/003921-0&mimeType=html&fmt=ahah

References

  1. Akins, R. A. ( 2005; ). An update on antifungal targets and mechanisms of resistance in Candida albicans. Med Mycol 43, 285–318.[CrossRef]
    [Google Scholar]
  2. Alvarez-Peral, F. J. & Argüelles, J.-C. ( 2000; ). Changes in external trehalase activity during human serum-induced dimorphic transition in Candida albicans. Res Microbiol 151, 837–843.[CrossRef]
    [Google Scholar]
  3. Alvarez-Peral, F. J., Zaragoza, O., Pedreno, Y. & Argüelles, J.-C. ( 2002; ). Protective role of trehalose during severe oxidative stress caused by hydrogen peroxide and the adaptive oxidative stress response in Candida albicans. Microbiology 148, 2599–2606.
    [Google Scholar]
  4. Argüelles, J. C. ( 2000; ). Physiological roles of trehalose in bacteria and yeasts: a comparative analysis. Arch Microbiol 174, 217–224.[CrossRef]
    [Google Scholar]
  5. Argüelles, J. C., Rodriguez, T. & Alvarez-Peral, F. J. ( 1999; ). Trehalose hydrolysis is not required for human serum-induced dimorphic transition in Candida albicans: evidence from a tps1/tps1 mutant deficient in trehalose synthesis. Res Microbiol 150, 521–529.[CrossRef]
    [Google Scholar]
  6. Bates, S., Hughes, H. B., Munro, C. A., Thomas, W. P. H., McCallum, D. M., Bertram, G., Atrih, A., Ferguson, M. A. J., Brown, A. J. P. & other authors ( 2006; ). Outer chain N-glycans are required for cell wall integrity and virulence of Candida albicans. J Biol Chem 281, 90–98.[CrossRef]
    [Google Scholar]
  7. Berman, J. & Sudbery, P. E. ( 2002; ). Candida albicans: a molecular revolution built on lessons from budding yeast. Nat Rev Genet 3, 918–930.
    [Google Scholar]
  8. Blázquez, M. A., Stucka, R., Feldmann, H. & Gancedo, C. ( 1994; ). Trehalose-6-P synthase is dispensable for growth on glucose but not for spore germination in Schizosaccharomyces pombe. J Bacteriol 176, 3895–3902.
    [Google Scholar]
  9. Calderone, R. A. & Fonzi, W. A. ( 2001; ). Virulence factors of Candida albicans. Trends Microbiol 9, 327–335.[CrossRef]
    [Google Scholar]
  10. Cannon, R. D., Timberlake, W. E., Gow, N. A. R., Bailey, D., Brown, A., Gooday, G. W., Hube, B., Monod, M., Nombela, C. & other authors ( 1994; ). Molecular biological and biochemical aspects of fungal dimorphism. J Med Vet Mycol 32 (Suppl. 1), 53–64.[CrossRef]
    [Google Scholar]
  11. Chauhan, N., Latge, J. P. & Calderone, R. ( 2006; ). Signalling and oxidant adaptation in Candida albicans and Aspergillus fumigatus. Nat Rev Microbiol 4, 435–444.[CrossRef]
    [Google Scholar]
  12. Denning, D. W. ( 2003; ). Echinocandin antifungal drugs. Lancet 362, 1142–1151.[CrossRef]
    [Google Scholar]
  13. Eck, R., Bergmann, C., Ziegelbauer, K., Schönfeld, W. & Künkel, K. ( 1997; ). A neutral trehalase gene from Candida albicans: molecular cloning, characterization and disruption. Microbiology 143, 3747–3756.[CrossRef]
    [Google Scholar]
  14. Eggimann, P., Garbino, J. & Pittet, D. ( 2003; ). Epidemiology of Candida species infections in critically ill non-immunosuppressed patients. Lancet Infect Dis 3, 685–702.[CrossRef]
    [Google Scholar]
  15. Elbein, A. D., Pan, Y. T., Pastuszak, I. & Carroll, D. ( 2003; ). New insights on trehalose: a multifunctional molecule. Glycobiology 13, 17R–27R.[CrossRef]
    [Google Scholar]
  16. Elorza, M. V., Murgui, A. & Sentandreu, R. ( 1985; ). Dimorphism in Candida albicans: contribution of mannoproteins to the architecture of yeast and mycelial cell walls. J Gen Microbiol 131, 2209–2216.
    [Google Scholar]
  17. Fonzi, W. A. & Irwin, M. Y. ( 1993; ). Isogenic strain construction and gene mapping in Candida albicans. Genetics 134, 717–728.
    [Google Scholar]
  18. Gietz, R. D., Schiestl, R. H., Willems, A. R. & Woods, R. A. ( 1995; ). Studies on the transformation of intact yeast cells by the LiAc/SS-DNA/PEG procedure. Yeast 11, 355–360.[CrossRef]
    [Google Scholar]
  19. González-Párraga, P., Hernández, J. A. & Argüelles, J. C. ( 2003; ). Role of antioxidant enzymatic defences against oxidative stress (H2O2) and the acquisition of oxidative tolerance in Candida albicans. Yeast 20, 1161–1169.[CrossRef]
    [Google Scholar]
  20. Gow, N. A. R., Brown, A. J. P. & Odds, F. C. ( 2002; ). Fungal morphogenesis and host invasion. Curr Opin Microbiol 5, 366–371.[CrossRef]
    [Google Scholar]
  21. Hernández, J. A., Campillo, A., Jiménez, A., Alarcón, J. J. & Sevilla, F. ( 1999; ). Response of antioxidant systems and leaf water relations to NaCl stress in pea plants. New Phytol 141, 241–251.[CrossRef]
    [Google Scholar]
  22. Hwang, C.-S., Rhie, G., Oh, J.-H., Huh, W.-K., Yim, H.-S. & Kang, S.-O. ( 2002; ). Copper- and zinc-containing superoxide dismutase (Cu/ZnSOD) is required for the protection of Candida albicans against oxidative stresses and the expression of its full virulence. Microbiology 148, 3705–3713.
    [Google Scholar]
  23. Kobayashi, S. D. & Cutler, J. E. ( 1998; ). Candida albicans hyphal formation and virulence: is there a clearly defined role? Trends Microbiol 6, 92–94.[CrossRef]
    [Google Scholar]
  24. Lo, H.-J., Köhler, 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]
  25. McNeil, M. M., Nash, S. L., Hajjeh, R. A., Phelan, M. A., Conn, L. A., Plikaytis, B. D. & Warnock, D. W. ( 2001; ). Trends in mortality due to invasive mycotic diseases in the United States, 1980-1997. Clin Infect Dis 33, 641–647.[CrossRef]
    [Google Scholar]
  26. Mukherjee, P. K., Sheehan, D. J., Hitchcock, C. A. & Ghannoum, M. A. ( 2005; ). Combination treatment of invasive fungal infections. Clin Microbiol Rev 18, 163–194.[CrossRef]
    [Google Scholar]
  27. Murad, A. M. A., Lee, P. R., Broadbent, I. D., Barelle, C. J. & Brown, A. J. P. ( 2000; ). CIp10, an efficient and convenient integrating vector for Candida albicans. Yeast 16, 325–327.[CrossRef]
    [Google Scholar]
  28. Odds, F. C. ( 1994; ). Candida species and virulence. ASM News 360, 313–318.
    [Google Scholar]
  29. Patterson, T. F. ( 2005; ). Advances and challenges in management of invasive mycoses. Lancet 366, 1013–1025.[CrossRef]
    [Google Scholar]
  30. Pedreño, Y., Maicas, S., Argüelles, J.-C., Sentandreu, R. & Valentin, E. ( 2004; ). The ATC1 gene encodes a cell wall-linked acid trehalase required for growth on trehalose in Candida albicans. J Biol Chem 279, 40852–40860.[CrossRef]
    [Google Scholar]
  31. Pedreño, Y., González-Párraga, P., Conesa, S., Martínez-Esparza, M., Aguinaga, A., Hernández, J. A. & Argüelles, J. C. ( 2006; ). The cellular resistance against oxidative stress (H2O2) is independent of neutral trehalase (Ntc1p) activity in Candida albicans. FEMS Yeast Res 6, 57–62.[CrossRef]
    [Google Scholar]
  32. Ram, S. P., Romana, L. K., Shepherd, M. G. & Sullivan, P. A. ( 1984; ). Exo-(1→3)-β-glucanase, autolysin and trehalase activities during yeast growth and germ-tube formation in Candida albicans. J Gen Microbiol 130, 1227–1236.
    [Google Scholar]
  33. Shepherd, M. G. ( 1985; ). Pathogenicity of morphological and auxotrophic mutants of Candida albicans in experimental infections. Infect Immun 50, 541–544.
    [Google Scholar]
  34. Singer, M. A. & Lindquist, S. ( 1998; ). Multiple effects of trehalose on protein folding in vitro and in vivo. Mol Cell 1, 639–648.[CrossRef]
    [Google Scholar]
  35. Sudbery, P., Gow, N. A. R. & Berman, J. ( 2004; ). The distinct morphogenic states of Candida albicans. Trends Microbiol 12, 317–324.[CrossRef]
    [Google Scholar]
  36. Thevelein, J. M. ( 1996; ). Regulation of trehalose metabolism and its relevance to cell growth and function. In The Mycota, vol. 3, pp. 395–414. Edited by R. Brambl & G. A. Marzluf. Heidelberg, Germany: Springer.
  37. 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.[CrossRef]
    [Google Scholar]
  38. Vázquez-Torres, A. & Balish, E. ( 1997; ). Macrophages in resistance to candidiasis. Microbiol Mol Biol Rev 61, 170–192.
    [Google Scholar]
  39. Verduyn Lunel, F. M., Meis, J. F. & Voss, A. ( 1999; ). Nosocomial fungal infections: candidemia. Diagn Microbiol Infect Dis 34, 213–220.[CrossRef]
    [Google Scholar]
  40. Zaragoza, O., Blazquez, M. A. & Gancedo, C. ( 1998; ). Disruption of the Candida albicans TPS1 gene encoding trehalose-6-phosphate synthase impairs formation of hyphae and decreases infectivity. J Bacteriol 180, 3809–3815.
    [Google Scholar]
  41. Zaragoza, O., de Virgilio, C., Ponton, J. & Gancedo, C. ( 2002; ). Disruption in Candida albicans of the TPS2 gene encoding trehalose-6-phosphate phosphatase affects cell integrity and decreases infectivity. Microbiology 148, 1281–1290.
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.2006/003921-0
Loading
/content/journal/micro/10.1099/mic.0.2006/003921-0
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error