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Eukaryotic Cell, August 2007, p. 1464-1473, Vol. 6, No. 8
1535-9778/07/$08.00+0     doi:10.1128/EC.00162-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Capsule Structural Heterogeneity and Antigenic Variation in Cryptococcus neoformans{triangledown}

Diane C. McFadden,1,{dagger} Bettina C. Fries,1,2 Fang Wang,3,{ddagger} and Arturo Casadevall1,2*

Department of Medicine, Division of Infectious Disease,1 Department of Microbiology and Immunology,2 Laboratory for Macromolecular Analysis and Proteomics, Albert Einstein College of Medicine, Bronx, New York 104613

Received 6 May 2007/ Accepted 2 June 2007

Cryptococcus neoformans is a human pathogenic fungus with a capsule composed primarily of glucuronoxylomannan (GXM) that is important for virulence. Current views of GXM structure postulate a polymer composed of repeating mannose trisaccharide motifs bearing a single ß(1,2) glucuronic acid with variable xylose and O-acetyl substitutions to form six triads. GXM from different strains is notoriously variable in triad composition, but it is not known if the polymer consists of one or more motif-repeating units. We investigated the polymeric organization of GXM by using mass spectrometry to determine if its compositional motif arrangement was similar to that of bacterial capsular polysaccharides, namely, a polymer of a single repeating unit. The results were consistent with, and confirmatory for, the current view that the basic unit of GXM is a repeating mannose trisaccharide motif, but we also found evidence for the copolymerization of different GXM repeating units in one polysaccharide molecule. Analysis of GXM from isogenic phenotypic switch variants suggested structural differences caused by glucuronic acid positional effects, which implied flexibility in the synthetic pathway. Our results suggest that cryptococcal capsule synthesis is fundamentally different from that observed in prokaryotes and employs a unique eukaryotic approach, which theoretically could synthesize an infinite number of structural combinations. The biological significance of this capsule construction scheme is that it is likely to confer a powerful avoidance strategy for interactions with the immune system and phagocytic environmental predators. Consistent with this premise, the antigenic variation of a capsular epitope recognized by a nonprotective antibody was observed under different growth conditions.

* Corresponding author. Mailing address: Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-3665. Fax: (718) 430-8701. E-mail: casadeva{at}aecom.yu.edu

{triangledown} Published ahead of print on 29 June 2007.

{dagger} Present address: Columbia University, 722 W. 168th Street, New York, NY 10032.

{ddagger} Present address: Wyeth Pharmaceuticals, Pearl River, NY 10965.

Eukaryotic Cell, August 2007, p. 1464-1473, Vol. 6, No. 8
1535-9778/07/$08.00+0     doi:10.1128/EC.00162-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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