The still obscure attributes of cryptococcal glucuronoxylomannan

Abstract

Glucuronoxylomannan (GXM) is the major capsular polysaccharide of Cryptococcus neoformans. It is essential for fungal virulence and causes a number of deleterious effects to host cells. During the last decades, most of the experimental models designed to study the roles of GXM during cryptococcal infection were based on the stimulation of animal cells. This most commonly involved macrophages or other effector cells, with polysaccharide fractions obtained by precipitation with cationic detergents. More recently, it has been demonstrated that GXM interferes with the physiological state of other target cells, such as the epithelium. In addition, recent studies indicate that the structure of the polysaccharide and, consequently, its functions vary according with the method used for its purification. This raises questions as to what is native GXM and the significance of prior studies. In this paper, we discuss some of the aspects of GXM that are still poorly explored in the current literature, including the relevance of the polysaccharide in the interaction of cryptococci with non-phagocytic cells and the relationship between its structure and biological activity.

Fig. 1

The putative functions of GXM during the infection of alveolar epithelial cells by Cryptococcus neoformans. (A) Once deposited into the alveolar space, C. neoformans is confronted by alveolar macrophages (not shown) or interact with epithelial cells (Panel 1). The adhesion of cryptococci to type II alveolar epithelial cells occurs via GXM binding to the CD14 receptor [29], in a process that is followed by fungal invasion (Panel 2) by still unknown mechanisms [27]. Phospholipase B (PLB), a membrane-damaging enzyme, is a potential candidate to mediate and/or amplify invasion (Panel 3), since its involvement in the interaction of C. neoformans with epithelial cells has already been demonstrated [26]. Prolonged interactions of Cryptococcus neoformans with the epithelial cells is known to induce host cell damage [27, 28], which may allow cryptococci to cross the epithelial barrier to reach the lung interstitium (Panel 4). B. The GXM-induced release of the proinflammatory chemokines IL-8 by epithelial cells could be associated with the recruitment of polymorphonuclear leukocytes (PMN) from the pulmonary vasculature into the alveolar space, as well as with stimulation of alveolar macrophages.

Fig. 2

GXM aggregation in the presence of divalent metals. GXM triads, comprising mannose (circules), xylose (triangles) and glucuronic acid (diamonds), are shown in the absence (A) or presence (B) of divalent cations. (C) Two residues of glucuronic acid are connected through one divalent cation. Viscosity, a parameter used to measure GXM aggregation, can be affected by different interfering agents (D).