New research published in Genes and Development from the Cormack lab shows that Candida glabrata has at least two groups of adhesin virulence genes located in subtelomeric regions that are regulated by a defined mechanism of transcriptional silencing.

Candida is responsible for 8% of serious nosocomial infections in the United States. In common with other Candida species, C. glabrata usually populates mucosal surfaces, but can breach the mucosal barrier when host defences are lowered and cause life threatening systemic infections. Unlike the diploid opportunistic pathogen Candida albicans, C. glabrata is haploid, which makes genetic manipulations far more straightforward. Previous work identified an adhesin protein — Epa1 — which enables C. glabrata to stick to epithelial cells. Epa1 is a member of a large class of cell wall proteins that are found in many fungi, including Saccharomyces and Aspergillus species.

When the EPA1 gene was deleted from the chromosome, the resulting mutant lost virtually all ability to attach to epithelial cells in the lab. So, EPA1 was an excellent candidate for a virulence gene. However, when the same mutant was tested for pathogenicity in mouse models of candidiasis it was still virulent. Pathogens like C. albicans, Trypansoma brucei and Plasmodium species commonly encode families of virulence genes. So, one possible solution to this conundrum was that C. glabrata might have a family of adhesins. The hunt was on for EPA1 homologues and now De Las Peñas et al. report the characterisation of 5 homologues of EPA1 in C. glabrata.

The 5 EPA1 homologues are located in two separate subtelomeric clusters. Although Saccharomyces cerevisiae and C. glabrata have largely similar genetic organisation (with syntenic gene arrangement) the subtelomeric regions, including the EPA genes, are completely different. Knocking out both subtelomeric EPA clusters reduced virulence of the resultant mutant strain in a mouse model. Genomic sequencing studies have subsequently uncovered additional potential EPA1 homologues, so the family is growing.

Curiously, De Las Peñas et al. found that only EPA1 was expressed in vitro. Not only were the other EPA genes repressed, but a marker gene — URA3 — was repressed when inserted at either subtelomeric locus. So, both subtelomeric EPA clusters are regionally silenced. This study also showed that a key component of the transcriptional silencing machinery in S. cerevisiae — SIR3 — regulates transcriptional silencing of the EPA genes in C. glabrata. Even though the telomere gene complements of these two fungi are different, the gene silencing mechanism is conserved between these species.

The subtelomeric location of the adhesin genes, coupled with a defined silencing mechanism, means that C. glabrata is the first pathogen for which the mechanism of transcriptional silencing of virulence factors has been defined. Intriguingly, regulation of subtelomeric silencing in S. cerevisiae has been linked to cellular stresses. Since cellular stress is likely to be common during infection, this raises the exciting possibility that C. glabrata virulence factors could be switched on and off during infections.