Cryptococcus neoformans and Cryptococcus gattii, the etiologic agents of cryptococcosis

Abstract

Cryptococcus neoformans and Cryptococcus gattii are the two etiologic agents of cryptococcosis. They belong to the phylum Basidiomycota and can be readily distinguished from other pathogenic yeasts such as Candida by the presence of a polysaccharide capsule, formation of melanin, and urease activity, which all function as virulence determinants. Infection proceeds via inhalation and subsequent dissemination to the central nervous system to cause meningoencephalitis. The most common risk for cryptococcosis caused by C. neoformans is AIDS, whereas infections caused by C. gattii are more often reported in immunocompetent patients with undefined risk than in the immunocompromised. There have been many chapters, reviews, and books written on C. neoformans. The topics we focus on in this article include species description, pathogenesis, life cycle, capsule, and stress response, which serve to highlight the specializations in virulence that have occurred in this unique encapsulated melanin-forming yeast that causes global deaths estimated at more than 600,000 annually.

Figure 1.

Route of cryptococcal meningoencephalitis. Airborne cryptococcal cells are inhaled by the host and proliferate in the lung before they hematogenously disseminate to the brain.

Figure 2.

Sexual and asexual states of Cryptococcus neoformans. (A) Yeast cells stained by India ink showing encapsulated globose cells. Scale bar, 5 µm. (B) Scanning electron micrograph of budding yeast cells (image courtesy of Sabriya Stukes). Scale bar, 1 µm. (C) Dikaryotic hyphal production (m) at the edge of mated strains between JEC20 (MATa) X JEC21(MATα). (D) Scanning electron micrograph of basidia-bearing chains of oval to elliptical basidiospores (Samson et al. 1983). Scale bar, 5 µm. (E) Life cycle of Cryptococcus neoformans. α, cells of MATα type; a, cells of MATa type.

Figure 3.

Sexual and asexual states of Cryptococcus gattii. (A) Basisia and basidiospores. Scale bar, 5 µm. (B) Globose to oval-shaped yeast cells of R265 (VGII type). (C) India ink–stained yeast cells of NIH319 (VGIII type). (D) Oval- to tear-shaped yeast cells of R-1407 (VGIV type). (E) CGB agar for differentiation of C. neoformans (no reaction) from C. gattii (cobalt blue).

Figure 4.

Structures of the cryptococcal capsular polysaccharide. The polymer repeat units of glucuronoxylomannan (GXM) and glucuronoxylomannogalactan (GXMGal) are shown. (Left) The maximally substituted structural reporter group of GXM. Other structural reporter groups vary in the extent and position of xylose addition (Cherniak et al. 1998). Mannose, green spheres; xylose, red stars; glucuronic acid, half-filled diamonds. Mannose acetylation is not shown. (Right) The repeat unit of glucuronoxylomannogalactan (GXMGal) (Vaishnav et al. 1998; Heiss et al. 2009). Trisaccharide side branches on alternate galactose residues may be modified with xylose and glucuronic acid; the two extremes of substitution are shown. Symbols are as above, with galactose as yellow spheres. A fraction of the branched backbone galactoses residues is also modified with β-1,2-linked galactofuranose, indicated by f; all other residues are in the pyranose form.

Figure 5.

The stress-signaling pathways in C. neoformans and C. gattii. The HOG pathway consists of a phosphorelay system (Tco, hybrid sensor histidine kinase [HHKs]; Ypd1, a His-containing phosphotransfer protein [HPt]; Ssk1, a response regulator [RR]) and a MAPK module; (Ssk2, MAPKKK; Pbs2, MAPKK; Hog1K, MAPK). The Mpk1 MAPK pathway, which is composed of Bck1 MAPKKK, Mkk2 MAPKK, and Mpk1 MAPK, appears to be activated by multiple upstream signaling pathways, including Pkc1 and Rho-type GTPases (Rho1, Rho11, and Rho10). Key components of the cAMP/PKA pathway include Cac1 and Aca1 for cAMP production and PKA, which consist of Pkr1 (a regulatory subunit) and Pka1/2 (catalytic subunits). Cac1 is activated by Gpa1 (a Gα subunit). Rim101 is a PKA-dependent transcription factor, which undergoes proteolysis for activation. Ras1 signaling bifurcates into Rac1, a G protein of the Rho family, and Cdc24, a guanine nucleotide exchange (GEF) factor. The calmodulin protein Cam1 binds Ca²⁺ via four EF-hand motifs and activates the Ser/Thr-specific phosphatase, calcineurin, which consists of Cna1 (a catalytic A subunit) and Cnb1 (a regulatory B subunit). The UPR pathway is composed of the Ire1 kinase, the bZIP transcription factor Hxl1, and their target genes, including KAR2. The described component functions of the signaling pathways are mainly derived from C. neoformans var. grubii. The components characterized in both C. gattii as well as C. neoformans are indicated in black boxes. The functions of these components in C. gattii are marked by a red line. Dotted arrows or line indicate potential but unclear regulation.