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Identification of pH-Regulated Antigen 1 Released from Candida albicans as the Major Ligand for Leukocyte Integrin _M2¹

Dmitry A. Soloviev^*, William A. Fonzi, Rafael Sentandreu, Elzbieta Pluskota^*, Christopher B. Forsyth^*, Satya Yadav^* and Edward F. Plow^2,*

^* Joseph J. Jacobs Center for Thrombosis and Vascular Biology and Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OH 44195; Department of Microbiology and Immunology, School of Medicine, Georgetown University, Washington, D.C. 20057; and Facultat de Farmacia, Universitat de Valencia, Burjassot València, Spain

Candida albicans is a common opportunistic fungal pathogen and is the leading cause of invasive fungal disease in immunocompromised individuals. The induction of cell-mediated immunity to C. albicans is of critical importance in host defense and the prime task of cells of the innate immune system. We previously demonstrated that the integrin _M2 (CD11b/CD18) is the major leukocyte receptor involved in C. albicans recognition, mediating both adhesive and migratory responses to the fungus. In the present study, we demonstrate that various C. albicans strains release a protease-sensitive activity into their conditioned medium that supports _M2-mediated cell adhesion and migration. The isolation and characterization of this protein was undertaken by two independent approaches: 1) immunoaffinity purification on a mAb raised to conditioned medium which blocked _M2-dependent adhesion and migration; and 2) affinity chromatography on purified _M2. Each approach led to the isolation of the same protein, which was unequivocally identified as pH-regulated Ag 1 (Pra1p), based on mass spectrometry and amino acid sequence analyses. C. albicans mutant strains lacking Pra1p were unable to support leukocyte adhesion or migration. In a neutrophil-mediated fungal killing assay, such mutant strains were resistant to killing and/or phagocytosis. Addition of purified Pra1p or reagents that block _M2 function prevented killing of Pra1p-expressing but not Pra1p-deficient strains of C. albicans. Together, these data indicate that Pra1p is a ligand of _M2 on C. albicans and that the soluble form of Pra1p may assist the fungus in escaping host surveillance.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ The work carried out in Valencia was partially supported by grants from the European Union (MRTN-CT-2003-504148) and the Spanish Ministerio de Ciencia y Tecnología (BMC2003-01023). Studies performed at the Cleveland Clinic were supported by National Institutes of Health Grant HL66197.

² Address correspondence and reprint requests to Dr. Edward F. Plow, Cleveland Clinic, 9500 Euclid Avenue, Mail Code NB50, Cleveland, OH 44195. E-mail address: plowe{at}ccf.org

³ Abbreviations used in this paper: PMN, polymorphonuclear neutrophil; PVP, polyvinylpyrrolidone; NIF, neutrophil inhibitory factor; Pra1p, pH-regulated Ag 1; CAS, C. albicans supernatant; CASL, C. albicans soluble ligand for _M2; RFU, relative fluorescence units.