Unraveling synthesis of the cryptococcal cell wall and capsule

Abstract

Fungal pathogens cause devastating infections in millions of individuals each year, representing a huge but underappreciated burden on human health. One of these, the opportunistic fungus Cryptococcus neoformans, kills hundreds of thousands of patients annually, disproportionately affecting people in resource-limited areas. This yeast is distinguished from other pathogenic fungi by a polysaccharide capsule that is displayed on the cell surface. The capsule consists of two complex polysaccharide polymers: a mannan substituted with xylose and glucuronic acid, and a galactan with galactomannan side chains that bear variable amounts of glucuronic acid and xylose. The cell wall, with which the capsule is associated, is a matrix of alpha and beta glucans, chitin, chitosan, and mannoproteins. In this review, we focus on synthesis of the wall and capsule, both of which are critical for the ability of this microbe to cause disease and are distinct from structures found in either model yeasts or the mammals afflicted by this infection. Significant research effort over the last few decades has been applied to defining the synthetic machinery of these two structures, including nucleotide sugar metabolism and transport, glycosyltransferase activities, polysaccharide export, and assembly and association of structural elements. Discoveries in this area have elucidated fundamental biology and may lead to novel targets for antifungal therapy. In this review, we summarize the progress made in this challenging and fascinating area, and outline future research questions.

The Fungal Cell Wall: Candida, Cryptococcus, and Aspergillus Species

“…Cryptococcus neoformans cell wall is a dynamic structure that undergoes constant remodeling to modulate the distribution and crosslinking of its components necessary for cellular growth and division (Doering, 2009;Agustinho et al, 2018;Wang et al, 2018). Cryptococcus cell wall is a two-layered structure composed by α-1,3-glucan, β-1,3 and β-1,6-glucan, chitin, chitosan, mannoproteins and other GPI-anchored proteins (Baker et al, 2007;Doering, 2009;O'Meara and Alspaugh, 2012;Wang et al, 2018). The inner layer is mainly composed of β-glucans and chitin arranged as fibers parallel to the plasma membrane and the outer layer contains α-glucan and β-glucan (Sakaguchi et al, 1993;Doering, 2009;O'Meara and Alspaugh, 2012; see Figure 2).…”

“…The exopolysaccharide capsule is anchored to the outer layer of the cell wall (O'Meara and Alspaugh, 2012;Wang et al, 2018) and this union needs to happen correctly since it is the main virulence factor of this yeast (Vecchiarelli, 2000;McFadden and Casadevall, 2001;Zaragoza et al, 2009). β-1,6-glucan is the most abundant component in Cryptococcus cell wall, while β-1,3glucan is less abundant, contrary to other yeasts (Gilbert et al, 2010;Wang et al, 2018). The main functions of β-1,6-glucan are to maintain and organize the cell wall through interactions with other cell wall components contributing to the integrity of Cryptococcus cell wall.…”

“…β-1,3-glucan synthase gene (FKS1) is essential, indicating the importance of this conserved cell wall component (Thompson et al, 1999;O'Meara and Alspaugh, 2012). By activating FKS1, Cryptococcus is able to respond to stress by producing β-1,3-glucan (Wang et al, 2018). The inhibition of β-1,3-glucan synthesis induces cell death and changes in cellular morphology (Toh et al, 2017).…”

Cryptococcosis

“…[29][30][31] Several important virulence factors have been identified for C. neoformans, but the most distinctive one is the polysaccharide capsule. [32][33][34][35][36][37] Although capsule production is a highly expensive metabolic process, it confers the organism several pathogenic advantages: it acts as a barrier against phagocytosis and complicates antibody response. Defects in capsule production generate avirulent strains.…”

Cryptococcus neoformansevades pulmonary immunity by modulating xylose precursor transport

“…In C. neoformans the major virulence factor, a polysaccharide capsule, modulates the immune response via multiple mechanisms (12, 13). The capsule is primarily composed of two large polysaccharides: glucuronoxylomannan (GXM) and glucuronoxylomannogalactan (GXMGal) (14, 15). One major component of both polymers is xylose (Xyl), which comprises almost one fourth of the polysaccharide capsule mass (16).…”