Sexual reproduction is a common attribute of eukaryotes owing to its potential to generate variability among individuals and to provide an advantage over species that are strictly asexual. Human pathogens are in a constant evolutionary 'arms race' with their hosts and sexual reproductive strategies enable these species to 'keep up'.
Accumulating genetic evidence suggests that most human fungal pathogens retain sexual reproductive machinery, and recent studies into their life cycles have detailed the sexual programmes of these fungi. It is becoming evident that most, it not all, of these species undergo cryptic sex.
We discuss the sexual cycles of three of the most prominent human pathogens — Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. Although the main tenets of sexual reproduction are conserved, these species exhibit specialized sexual programmes, including transitions from heterothallism to homothallism and from sexual to parasexual reproduction, giving an enigmatic aspect to fungal sexual cycles.
Although most fungal pathogens have retained the ability to mate, these species seem to promote inbreeding and the conservation of highly adapted pathogenic strains, which results in largely clonal populations.
Sexual reproduction in these species can directly affect pathogenesis via the generation of genetic variants, the emergence of drug-resistant isolates or the modulation of interactions with host cells. The mechanisms that regulate fungal sexual reproduction, as well as the consequences of these specialized programs for host–pathogen interactions, are important as they reveal strategies that enable fungi to survive, mate, colonize and infect the mammalian host.
Sexual reproduction is a pervasive attribute of eukaryotic species and is now recognized to occur in many clinically important human fungal pathogens. These fungi use sexual or parasexual strategies for various purposes that can have an impact on pathogenesis, such as the formation of drug-resistant isolates, the generation of strains with increased virulence or the modulation of interactions with host cells. In this Review, we examine the mechanisms regulating fungal sex and the consequences of these programmes for human disease.
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The authors thank J. Heitman for comments and suggestions on the manuscript. They also thank M. Hirakawa, E. Byrnes, J. Heitman, C. O'Gorman and P. Dyer for providing scanning electron micrographs. I.V.E. is supported by a Vessa Notchev Fellowship from Sigma Delta Epsilon-Graduate Women in Science (SDE-GWIS). Work in the laboratory of R.J.B. is supported by a US National Institutes of Health grant AI081704 and by the National Science Foundation grant 1021120 to R.J.B. R.J.B. also holds an Investigator in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund.
The authors declare no competing financial interests.
Modes of sexual reproduction in fungi. (PDF 697 kb)
Mating type loci in the three most common human pathogenic fungi. (PDF 268 kb)
Phylogenetic tree of fungal species including those commonly associated with human disease (PDF 228 kb)
- Parasexual reproduction
Form of reproduction in which transfer of genetic material and recombination occurs without meiosis or the development of sexual structures.
- Muller's ratchet
The accumulation of deleterious mutations in an asexual population, which becomes so great that it leads to the extinction of the population.
The largest division in the fungal kingdom; they are commonly known as sac fungi. Their name stems from their defining sexual feature, ascus (in the form of an ascocarp or cleistothecium), which is where nuclear fusion and meiosis take place, resulting in the formation of ascospores.
One of the two large phyla of Fungi that are typically known as higher fungi. They are most commonly filamentous fungi that reproduce sexually by forming round-shaped cells known as basidia, which bear external basidiospores.
A 60 amino acid protein domain that folds into a helix–turn–helix compact structure and binds to DNA. Homeodomain folds are commonly found in transcription factors and they are found exclusively in eukaryotes, where they often induce cellular differentiation.
(Mitogen-activated protein kinase). A serine/threonine-specific protein kinase that signals cellular responses to a wide range of stimuli, including pheromones, mitogens, osmotic or heat stress.
A change in chromosome copy number that does not parallel a change in the entire haploid or diploid genome.
Complex communities of microorganisms that are commonly found attached to a prosthetic surface in the host. Cells adhere to the surface and to each other and promote the formation of extracellular matrix, which protects the biofilm community from external stress (including antifungal drugs).
- Gastrointestinally induced transition
(GUT). A phenotypic transition that enables C. albicans cells to hypercolonize the gastrointestinal tracts of mice.
- Candida clade
A group of related Candida species; members of this group share an altered genetic code in which the CUG codon is translated as leucine instead of serine as in the universal genetic code. This group includes most pathogenic Candida species, except for Candida glabrata, which is more closely related to Saccharomyces cerevisiae.
Distinct fungal mating type genes, which, in contrast to alleles, generally lack homology and do not seem to share an obvious ancestry.
(High mobility group-box). A protein domain that is involved in DNA binding.
- Dimorphic fungi
Fungi that can exist as single cells (yeast) or in a hyphal or filamentous form. Morphological transitions, such as the yeast–hyphal transition, are driven by a range of environmental conditions (for example, temperature or pH).
A phylum of fungi whose name derives from zygospores, which are resistant spherical spores that are formed during mating. Species include Mucor circinelloides and Rhizopus stolonifer, which is the black bread mould.
The close relationship between two organisms, in which one organism (the commensal organism) benefits without affecting its host. The term is derived from the Latin 'commensalis', which means 'sharing a table'.
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Ene, I., Bennett, R. The cryptic sexual strategies of human fungal pathogens. Nat Rev Microbiol 12, 239–251 (2014). https://doi.org/10.1038/nrmicro3236
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