Fungal sex and pathogenesis

Abstract

Human fungal pathogens are associated with diseases ranging from dandruff and skin colonization to invasive bloodstream infections. The major human pathogens belong to the Candida, Aspergillus, and Cryptococcus clades, and infections have high and increasing morbidity and mortality. Many human fungal pathogens were originally assumed to be asexual. However, recent advances in genome sequencing, which revealed that many species have retained the genes required for the sexual machinery, have dramatically influenced our understanding of the biology of these organisms. Predictions of a rare or cryptic sexual cycle have been supported experimentally for some species. Here, I examine the evidence that human pathogens reproduce sexually. The evolution of the mating-type locus in ascomycetes (including Candida and Aspergillus species) and basidiomycetes (Malassezia and Cryptococcus) is discussed. I provide an overview of how sex is suppressed in different species and discuss the potential associations with pathogenesis.

FIG. 1.

Fungal phylogeny. The tree shows the phylogeny of 42 fungi with fully sequenced genomes. Plant pathogens are indicated in blue, and human pathogens are in red. (Adapted from reference .)

FIG. 2.

(A) Organization of the mating-type-like locus in the Candida clade. MTLα-specific genes are shown in black and MTLa-specific genes in gray. Orthologs are indicated in color and are connected by gray lines. The MTL locus in C. dubliniensis is inverted relative to that in C. albicans. For heterothallic species, both idiomorphs are shown, joined by a curly bracket. No MTLα idiomorph of C. parapsilosis has been identified, and no mating genes have been identified in L. elongisporus. P stipitis, D. hansenii, and L. elongisporus are assumed to be homothallic. ORF, open reading frame. (Adapted from reference , with data from references , , , , , and .) (B) Gene losses are indicated on the Candida clade phylogeny.

FIG. 3.

Comparison of STE2 (α-factor receptor) sequences from the Candida clade and from S. cerevisiae. The IC1 and EC1 domains described by Yi et al. (271) are unique to C. albicans and C. dubliniensis. Motif IC1 is required for the white cell response to α pheromone.

FIG. 4.

Organization of the mating-type-like locus in the aspergilli. The α-box domain proteins (MAT1-1-1) are shown in red and the HMG domain proteins (MAT1-2-1) in green. The MTL organization in homothallic species is circled in gray. Alternative idiomorphs in the heterothallic species are shown by an offset box below the α idiomorph. Some genes (such as MAT1-2-4 in A. fumigatus and other species) are omitted for clarity. A question mark indicates that the sequence of the MTLa-like idiomorph has not been sequenced, but isolates have been reported (64). (Based on data from references , , and and http:/www.broadinstitute.org. The schematic phylogeny is based on data from references and .)

FIG. 5.

The pheromone response pathway in fungi. The pathway in S. cerevisiae is shown; there are differences in other fungi, but the core MAP kinase pathway is conserved. Genes in which disruptions affect virulence of human pathogens are indicated.