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Histoplasma capsulatum Cyclophilin A Mediates Attachment to Dendritic Cell VLA-5¹

Francisco J. Gomez^2,*,, Robyn Pilcher-Roberts^*,, Arash Alborzi^* and Simon L. Newman^*

^* Department of Internal Medicine, Division of Infectious Diseases, University of Cincinnati College of Medicine, and Veterans Administration Medical Center, Cincinnati, OH 45267

Histoplasma capsulatum (Hc) is a pathogenic fungus that replicates in macrophages (M). In dendritic cells (DC), Hc is killed and fungal Ags are processed and presented to T cells. DC recognize Hc yeasts via the VLA-5 receptor, whereas M recognize yeasts via CD18. To identify ligand(s) on Hc recognized by DC, VLA-5 was used to probe a Far Western blot of a yeast freeze/thaw extract (F/TE) that inhibited Hc binding to DC. VLA-5 recognized a 20-kDa protein, identified as cyclophilin A (CypA), and CypA was present on the surface of Hc yeasts. rCypA inhibited the attachment of Hc to DC, but not to M. Silencing of Hc CypA by RNA interference reduced yeast binding to DC by 65–85%, but had no effect on binding to M. However, F/TE from CypA-silenced yeasts still inhibited binding of wild-type Hc to DC, and F/TE from wild-type yeasts depleted of CypA also inhibited yeast binding to DC. rCypA did not further inhibit the binding of CypA-silenced yeasts to DC. Polystyrene beads coated with rCypA or fibronectin bound to DC and M and to Chinese hamster ovary cells transfected with VLA-5. Binding of rCypA-coated beads, but not fibronectin-coated beads, was inhibited by rCypA. These data demonstrate that CypA serves as a ligand for DC VLA-5, that binding of CypA to VLA-5 is at a site different from FN, and that there is at least one other ligand on the surface of Hc yeasts that mediates binding of Hc to DC.

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 This work was supported by U.S. Public Health Service Grants AI49358 and AI061298 from the National Institutes of Allergy and Infectious Diseases.

² Address correspondence and reprint requests to Dr. Francisco Gomez, Division of Infectious Diseases, University of Cincinnati College of Medicine, P.O. Box 670560, Cincinnati, OH 45267. E-mail address: francisco.gomez{at}uc.edu

³ Abbreviations used in this paper: Hc, Histoplasma capsulatum; M, macrophage; DC, dendritic cell; CypA, cyclophilin A; F/TE, freeze/thaw extract; WT, wild type; FN, fibronectin; HK, heat killed; Sc, Saccharomyces cerevisiae; HSP60, heat shock protein 60; CHO, Chinese hamster ovary; 1D, one dimensional; 2D, two dimensional; AI, attachment index; PPIase, peptidyl-prolyl cis-trans isomerase; Mip, M infectivity potentiator.

⁴ The online version of this article contains supplemental material.