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Binding and Internalization of Glucuronoxylomannan, the Major Capsular Polysaccharide of Cryptococcus neoformans, by Murine Peritoneal Macrophages

Zong Liang Chang,^1,2 Dale Netski,^1, Peter Thorkildson,¹ and Thomas R. Kozel^1*

Department of Microbiology and Immunology, University of Nevada School of Medicine, Reno, Nevada 89557,¹ Laboratory of Immune Signal Transduction, Institute of Biochemistry and Cell Biology, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China²

Received 26 August 2005/ Returned for modification 29 September 2005/ Accepted 26 October 2005

Glucuronoxylomannan (GXM), the major component of the capsular polysaccharide of Cryptococcus neoformans, is essential to virulence of the yeast. Previous studies found that the interaction between GXM and phagocytic cells has biological consequences that may contribute to the pathogenesis of cryptococcosis. We found that GXM binds to and is taken up by murine peritoneal macrophages. Uptake is dose and time dependent. Examination of the sites of GXM accumulation by immunofluorescence microscopy showed that the pattern was discontinuous and punctate both on the surfaces of macrophages and at intracellular depots. Although resident macrophages showed appreciable accumulation of GXM, uptake was greatest with thioglycolate-elicited macrophages. A modest stimulation of GXM binding followed treatment of resident macrophages with phorbol 12-myristate 13-acetate, but treatment with lipopolysaccharide or gamma interferon alone or in combination had no effect. Accumulation of GXM was critically dependent on cytoskeleton function; a near complete blockade of accumulation followed treatment with inhibitors of actin. GXM accumulation by elicited macrophages was blocked by treatment with inhibitors of tyrosine kinase, protein kinase C, and phospholipase C, but not by inhibitors of phosphatidylinositol 3-kinase, suggesting a critical role for one or more signaling pathways in the macrophage response to GXM. Taken together, the results demonstrate that it is possible to experimentally enhance or suppress binding of GXM to macrophages, raising the possibility for regulation of the interaction between this essential virulence factor and binding sites on cells that are central to host resistance.

Editor: A. Casadevall

Present address: Division of Infectious Diseases, John's Hopkins University School of Medicine, 424 N. Bond St., Room 104, Baltimore, MD 21205.

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