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Infection and Immunity, May 2007, p. 2126-2135, Vol. 75, No. 5
0019-9567/07/$08.00+0     doi:10.1128/IAI.00054-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Mucosal Tissue Invasion by Candida albicans Is Associated with E-Cadherin Degradation, Mediated by Transcription Factor Rim101p and Protease Sap5p{triangledown}

C. C. Villar,1* H. Kashleva,1 C. J. Nobile,2 A. P. Mitchell,2 and A. Dongari-Bagtzoglou1

Department of Periodontology, School of Dental Medicine, University of Connecticut, Farmington, Connecticut 06030-1710,1 Department of Microbiology, Columbia University, New York, New York 100322

Received 10 January 2007/ Returned for modification 3 February 2007/ Accepted 18 February 2007

The ability of Candida albicans to invade mucosal tissues is a major virulence determinant of this organism; however, the mechanism of invasion is not understood in detail. Proteolytic breakdown of E-cadherin, the major protein in epithelial cell junctions, has been proposed as a mechanism of invasion of certain bacteria in the oral mucosa. The objectives of this study were (i) to assess whether C. albicans degrades E-cadherin expressed by oral epithelial cells in vitro; (ii) to compare the abilities of strains with different invasive potentials to degrade this protein; and (iii) to investigate fungal virulence factors responsible for E-cadherin degradation. We found that while E-cadherin gene expression was not altered, E-cadherin was proteolytically degraded during the interaction of oral epithelial cells with C. albicans. Moreover, C. albicans-mediated degradation of E-cadherin was completely inhibited in the presence of protease inhibitors. Using a three-dimensional model of the human oral mucosa, we found that E-cadherin was degraded in localized areas of tissue invasion by C. albicans. An invasion-deficient rim101–/rim101– strain was deficient in degradation of E-cadherin, and this finding suggested that proteases may depend on Rim101p for expression. Indeed, reverse transcription-PCR data indicated that expression of the SAP4, SAP5, and SAP6 genes is severely reduced in the rim101–/rim101– mutant. These SAP genes are functional Rim101p targets, because engineered expression of SAP5 in the rim101–/rim101– strain restored E-cadherin degradation and invasion in the mucosal model. Our data support the hypothesis that there is a mechanism by which C. albicans invades mucosal tissues by promoting the proteolytic degradation of E-cadherin in epithelial adherens junctions.

* Corresponding author. Mailing address: Department of Periodontology, School of Dental Medicine, University of Connecticut, 263 Farmington Ave., Farmington, CT 06030-1710. Phone: (860) 679-3722. Fax: (860) 679-1673. E-mail: cvillar{at}uchc.edu

{triangledown} Published ahead of print on 5 March 2007.

Editor: A. Casadevall

Infection and Immunity, May 2007, p. 2126-2135, Vol. 75, No. 5
0019-9567/07/$08.00+0     doi:10.1128/IAI.00054-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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