Comparative genomics of emerging pathogens in the Candida glabrata clade

Abstract

BackgroundCandida glabrata follows C. albicans as the second or third most prevalent cause of candidemia worldwide. These two pathogenic yeasts are distantly related, C. glabrata being part of the Nakaseomyces, a group more closely related to Saccharomyces cerevisiae. Although C. glabrata was thought to be the only pathogenic Nakaseomyces, two new pathogens have recently been described within this group: C. nivariensis and C. bracarensis. To gain insight into the genomic changes underlying the emergence of virulence, we sequenced the genomes of these two, and three other non-pathogenic Nakaseomyces, and compared them to other sequenced yeasts.ResultsOur results indicate that the two new pathogens are more closely related to the non-pathogenic N. delphensis than to C. glabrata. We uncover duplications and accelerated evolution that specifically affected genes in the lineage preceding the group containing N. delphensis and the three pathogens, which may provide clues to the higher propensity of this group to infect humans. Finally, the number of Epa-like adhesins is specifically enriched in the pathogens, particularly in C. glabrata.ConclusionsRemarkably, some features thought to be the result of adaptation of C. glabrata to a pathogenic lifestyle, are present throughout the Nakaseomyces, indicating these are rather ancient adaptations to other environments. Phylogeny suggests that human pathogenesis evolved several times, independently within the clade. The expansion of the EPA gene family in pathogens establishes an evolutionary link between adhesion and virulence phenotypes. Our analyses thus shed light onto the relationships between virulence and the recent genomic changes that occurred within the Nakaseomyces.Sequence Accession NumbersNakaseomyces delphensis: CAPT01000001 to CAPT01000179Candida bracarensis: CAPU01000001 to CAPU01000251Candida nivariensis: CAPV01000001 to CAPV01000123Candida castellii: CAPW01000001 to CAPW01000101Nakaseomyces bacillisporus: CAPX01000001 to CAPX01000186

Structural Hot Spots Determine Functional Diversity of the Candida glabrata Epithelial Adhesin Family

“…It is interesting to note that the DD-N calcium-binding signature can be found in over 85% of the estimated 200 Epa-like domains that are currently present in the known fungal genome sequences. 5 In contrast, the W-R signature is highly restricted to the Epa-like adhesins of the "glabrata group" of Nakaseomyces species, including C. glabrata, C. bracarensis, C. nivariensis, and N. delphensis (19), and can be found in only very few Epa-like orthologs from other fungi. Therefore, the W-R signature is a hallmark of the glabrata group and might have evolved in a close ancestor of this group of Nakaseomyces.…”

“…10), suggesting that their binding specificities differ from C. glabrata Epa adhesins. Thus, specific adaptation of the CBL2 motifs of Epa adhesins might have evolved after the DD-N and W-R core motifs and account for the differences in host specificities observed for the different members of the glabrata group of Nakaseomyces (19,46). It is important to point out, however, that residues outside the CBL2 region must also contribute to ligand binding specificity, given the fact that we found four cases in which two different Epa proteins have identical CBL2 motifs but distinct ligand-binding patterns.…”

“…The largest group comprises the EPA (epithelial adhesin) family that, depending on the strain, contains between 17 (CBS138) and 23 (BG2) members (17,18). Epa-like adhesins are also present in other species of the Nakaseomyces genus, a group of six yeasts that include C. glabrata and whose genomes have recently been sequenced (19). Remarkably, the two other human pathogenic Nakaseomyces, Candida bracarensis and Candida nivariensis, contain 12 and 9 EPA-like genes, respectively, whereas only a single copy can be found in the nonpathogenic Nakaseomyces delphensis.…”

Mating-type switching by chromosomal inversion in methylotrophic yeasts suggests an origin for the three-locusSaccharomyces cerevisiaesystem

“…1). Genome sequences show that almost all species in this family have three MAT-like loci and are likely to switch mating types by a mechanism similar to that of S. cerevisiae (8,29,34,35), although some species use an alternative mechanism instead of HO endonuclease to cut the MAT locus (15). Family Saccharomycetaceae is one clade within the subphylum Saccharomycotina, which also includes a large clade of Candida and related species (called the "CTG clade" because of its unusual genetic code).…”

Competition ofCandida glabrataagainstLactobacillusis Hog1 dependent

“…In the northern hemisphere, Candida albicans and Candida glabrata are the two most common species isolated from VVC patients. C. glabrata belongs to the Nakaseomyces group, which includes other pathogenic yeasts and is phylogenetically related to Saccharomyces cerevisiae (Gabaldon et al, 2013). The intrinsic resistance of C. glabrata to fluconazole (and occasional resistance to echinocandins) advanced C. glabrata to the second most isolated Candida spp.…”