Microbial Pathogens in the Fungal Kingdom

Abstract

The fungal kingdom is vast, spanning ~1.5 to as many as 5 million species diverse as unicellular yeasts, filamentous fungi, mushrooms, lichens, and both plant and animal pathogens. The fungi are closely aligned with animals in one of the six to eight supergroups of eukaryotes, the opisthokonts. The animal and fungal kingdoms last shared a common ancestor ~1 billion years ago, more recently than other groups of eukaryotes. As a consequence of their close evolutionary history and shared cellular machinery with metazoans, fungi are exceptional models for mammalian biology, but prove more difficult to treat in infected animals. The last common ancestor to the fungal/metazoan lineages is thought to have been unicellular, aquatic, and motile with a posterior flagellum, and certain extant species closely resemble this hypothesized ancestor. Species within the fungal kingdom were traditionally assigned to four phyla, including the basal fungi (Chytridiomycota, Zygomycota) and the more recently derived monophyletic lineage, the dikarya (Ascomycota, Basidiomycota). The fungal tree of life project has revealed that the basal lineages are polyphyletic, and thus there are as many as eight to ten fungal phyla. Fungi that infect vertebrates are found in all of the major lineages, and virulence arose multiple times independently. A sobering recent development involves the species Batrachochytrium dendrobatidis from the basal fungal phylum, the Chytridiomycota, which has emerged to cause global amphibian declines and extinctions. Genomics is revolutionizing our view of the fungal kingdom, and genome sequences for zygomycete pathogens (Rhizopus, Mucor), skin-associated fungi (dermatophytes, Malassezia), and the Candida pathogenic species clade promise to provide insights into the origins of virulence. Here we survey the diversity of fungal pathogens and illustrate key principles revealed by genomics involving sexual reproduction and sex determination, loss of conserved pathways in derived fungal lineages that are retained in basal fungi, and shared and divergent virulence strategies of successful human pathogens, including dimorphic and trimorphic transitions in form. The overarching conclusion is that fungal pathogens of animals have arisen repeatedly and independently throughout the fungal tree of life, and while they share general properties, there are also unique features to the virulence strategies of each successful microbial pathogen.

Figure 1. The eukaryotic tree of life

Recent molecular phylogenetic studies revealed the organization of the eukaryotic domains of life stemming from a last common ancestor. In particular, this analysis revealed a unique evolutionary relationship of the fungi and the animals as opisthokonts, sharing a more recent last common ancestor with each other to the exclusion of all other groups of eukaryotes. Modified from Baldauf et al, Science 2003.

Figure 2. Microbial pathogens in the diverse phyla of the fungal kingdom

Based on the AFTOL project, we now appreciate that the fungal kingdom spans as many as 10 phyla (the microsporidia are not depicted here) (James et al., 2006). Fungal pathogens have evolved repeatedly and independently throughout these phyla, and specific examples discussed in this review are depicted here. Adapted from Figure 1 from Schussler et al, Mycological Research 2001.

Figure 3. Opposite- and same-sex mating pathways in C. neoformans and C. albicans

Recent studies reveal that these two common human fungal pathogens have retained extant sexual cycles involving cells of either opposite mating type or the same mating type. In C. neoformans, both sexual cycles are complete, including meiotic recombination, and generate infectious haploid spores. C. albicans is an obligate diploid, and mating first requires homozygosis of the MAT locus to produce or α/α or a/a cells, which undergo white to opaque switching and then fuse to produce a tetraploid zygote that undergoes concerted random chromosome loss to return to the diploid state by a currently recognized parasexual cycle. Same-sex mating can occur in strains lacking the Bar1 protease that destroys α factor, or in the presence of limiting α cells as a pheromone donor. The parasexual cycle of C. albicans involves Spo11-dependent recombination, and therefore may also involve cryptic versions of meiosis.

Figure 4. Trimorphic transitions in C. albicans

The left panel depicts the transition of C. albicans yeast cells to pseudohyphae (left) and hyphae (right) as two distinct developmental fates. The right panel depicts this trimorphic transition as a continuum from yeast to pseudohyphae to hyphae. Recent studies support the continuum model of development. Modified from Figures 5.2, 5.3, and 5.4 from Odds 1988 with permission.