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Infection and Immunity, May 2005, p. 2758-2765, Vol. 73, No. 5
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.5.2758-2765.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Candida albicans-Secreted Aspartic Proteinases Modify the Epithelial Cytokine Response in an In Vitro Model of Vaginal Candidiasis

Martin Schaller,1,2* Hans C. Korting,1 Claudia Borelli,1 Gerald Hamm,3 and Bernhard Hube4

Department of Dermatology and Allergology, University of Munich, Munich,1 Department of Dermatology, University of Tuebingen, Tuebingen,2 Department of Parodontology, University of Munich, Munich,3 Robert Koch-Institut, Berlin, Germany4

Received 12 August 2004/ Returned for modification 18 October 2004/ Accepted 17 December 2004

Secreted aspartyl proteinases (Saps) are important virulence factors of Candida albicans during mucosal and disseminated infections and may also contribute to the induction of an inflammatory host immune response. We used a model of vaginal candidiasis based on reconstituted human vaginal epithelium (RHVE) to study the epithelial cytokine response induced by C. albicans. In order to study the impact of the overall proteolytic activity and of distinct Sap isoenzymes, we studied the effect of the proteinase inhibitor pepstatin A on the immune response and compared the cytokine expression pattern induced by the wild-type strain SC5314 with the pattern induced by Sap-deficient mutants. Infection of RHVE with the C. albicans wild-type strain induced strong interleukin 1{alpha} (IL-1{alpha}), IL-1ß, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, gamma interferon, and tumor necrosis factor alpha responses in comparison with cytokine expression in noninfected tissue. Addition of the aspartyl proteinase inhibitor pepstatin A strongly reduced the cytokine response of RHVE. Furthermore, SAP-null mutants lacking either SAP1 or SAP2 caused reduced tissue damage and had a significantly reduced potential to stimulate cytokine expression. In contrast, the vaginopathic and cytokine-inducing potential of mutants lacking SAP4 to SAP6 was similar to that of the wild-type strain. These data show that the potential of specific Saps to cause tissue damage correlates with an epithelium-induced proinflammatory cytokine response, which may be crucial in controlling and managing C. albicans infections at the vaginal mucosa in vivo.

* Corresponding author. Mailing address: Department of Dermatology, Eberhard Karls University Tuebingen, Liebermeisterstrasse 25, 72076 Tuebingen, Germany. Phone: 49 7071 2984555. Fax: 49 7071 298 5113. E-mail: Martin.Schaller{at}med.uni-tuebingen.de.

Editor: T. R. Kozel

Infection and Immunity, May 2005, p. 2758-2765, Vol. 73, No. 5
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.5.2758-2765.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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