Through a glass opaquely: the biological significance of mating in Candida albicans

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Most Candida albicans strains are heterozygous at the MTL (mating-type-like) locus, but mating occurs in hemi- or homozygous strains. The white–opaque switch process is repressed by the heterodimer of the MTLa1 and MTLα2 gene products, while mating genes are induced by a2 and α1. Mating occurs in opaque cells and produces tetraploid progeny. A small percentage (3–7%) of clinical isolates are homozygous at the MTL locus and most are mating-competent. MTL gene expression is controlled in part by a gene which activates MTLα genes and represses MTLa genes in response to hemoglobin. A failure to find meiosis and the lack of evidence of mating in vivo, together with some of the properties of opaque cells, leads to the suggestion that mating may have persisted because the tightly associated switch facilitates the commensal lifestyle of this fungus.

Introduction

For over 100 years Candida albicans was considered asexual, and attention was focused on its pathogenic potential. Although the fundamental biological niche of C. albicans is as a commensal in warm-blooded animals, especially primates, it was the first fungus to be associated with human disease, almost exclusively skin and mucosal infections. Aggressive medical interventions resulting in debilitated and immunocompromised patients have led to disseminated, life-threatening candidiasis and stimulated efforts to identify virulence factors, develop genetic tools, and explore the mechanisms of pathogenesis of C. albicans. One of the early results was the finding that C. albicans as usually isolated is diploid 1., 2., 3.. Another fruit of these efforts was the determination of the sequence of the genome [4]. Analysis of the sequence led to the discovery of a mating type locus [5] and subsequently to the demonstration of mating of laboratory strains 6., 7.. Mating so far has been shown only to occur in laboratory experiments.

In this review, we discuss the progress that has been made in elucidating the mating process and the functions of the MTL locus and examine the implications of this work for the complex biology of this opportunistic pathogen. We pose the question of whether mating itself or the complex of properties associated with it, including the white–opaque switch and the properties regulated by the MTL genes, may account for the preservation of mating in this predominately diploid organism.

Section snippets

Requirements for mating

It is not surprising that C. albicans was long thought to be asexual, as its requirements for mating are more complex than for most fungi. The discovery of a mating-type ortholog in the emerging genomic sequence in 1999 led Hull and Johnson to identify two mating-type loci, MTLa and MTLα (for mating-type-like) [5]. MTLα has two functional genes, α1 and α2; MTLa, originally thought to have only a1, now is known to contain a1 and a2 [8••]. Functional hemizygosity or homozygosity at the mating

The stages of mating

Lockhart et al., using strains identified in their collection of clinical isolates as homozygous MTLa or MTLα (see below), carried out a detailed examination of the mating process [21••]. They divided mating into several stages, beginning with shmooing, continuing through conjugation tube extension and fusion, and ending with daughter cell septation (reviewed in [22] and [23]). Although they were able to characterize in detail the various stages of cell fusion, they did not observe nuclear

Mating of clinical isolates

Although most of the laboratory strains examined have been found to be heterozygous at the MTL locus, three laboratories have found homozygotes among their collections. Rustad et al. found six MTLa/MTLa and six MTLα/MTLα strains among 96 isolates [25]. Forty-six of the total sample and eleven of the MTL homozygotes were fluconazole-resistant. At least part of the explanation for the association is the synteny of the MTL locus with two genes on chromosome 5: the target gene for fluconazole which

Mating potential and host interaction

Among the more interesting unanswered questions about mating is whether it has any significance in the host–commensal/parasite relationship. Does mating occur in vivo? Are some configurations at the MTL locus more virulent or better fitted for commensalism than the other two? Do tetraploids occur in vivo, and if they do, are they more or less virulent than diploids of the same genotype? Many of these questions have not been answered at the present time. However, some interesting data suggest

Why has mating capacity been conserved?

An organized process for the reduction of ploidy after mating has not yet been discovered and tetraploids have not been found among clinical isolates, so does Candida albicans ever mate outside the laboratory? And if not, why conserve the capacity to mate? In fact, what have been conserved are intact, heterozygous MTL alleles. In a heterozygous strain, switching and sensitivity to mating hormones are almost always repressed, but many of the non-mating genes whose expression is regulated by one

Conclusions

Mating in C. albicans has several overall similarities to mating in S. cerevisiae, but there are significant differences, including the genetic structure of the MTLa locus, where an additional gene, a2, is required to activate the a-specific genes. Most importantly, mating in Candida requires the white–opaque phenotypic switch, a transition between two significantly different cell phenotypes that is repressed by the MTLa1/α2 heterodimer. Although mating is efficient in the laboratory, it seems

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We are grateful to Dana Davis for reading the manuscript. Work from the Magee laboratory described here was supported by grant AI16567 from the National Institute of Allergy and Infectious Disease.

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