TheCandida albicansreference strain SC5314 contains a rare, dominant allele of the transcription factor Rob1 that modulates biofilm formation and oral commensalism

Abstract

AbstractCandida albicansis a diploid human fungal pathogen that displays significant genomic and phenotypic heterogeneity over a range of virulence traits and in the context of a variety of environmental niches. Here, we show that the effects of Rob1 on biofilm and filamentation virulence traits is dependent on both the specific environmental condition and the clinical strain ofC. albicans. TheC. albicansreference strain SC5314 is aROB1heterozygote with two alleles that differ by a single nucleotide polymorphism at position 946 resulting in a serine or proline containing isoform. An analysis of 224 sequencedC. albicansgenomes indicates that SC5314 is the onlyROB1heterozygote documented to date and that the dominant allele contains a proline at position 946. Remarkably, theROB1alleles are functionally distinct and the rareROB1946Sallele supports increased filamentation in vitro and increased biofilm formation in vitro and in vivo, suggesting it is a phenotypic gain-of-function allele. SC5314 is amongst the most highly filamentous and invasive strains characterized to date. Introduction of theROB1946Sallele into a poorly filamenting clinical isolate increases filamentation and conversion of an SC5314 laboratory strain to aROB1946Shomozygote increases in vitro filamentation and biofilm formation. In a mouse model of oropharyngeal infection, the predominantROB1946Pallele establishes a commensal state while theROB1946Sphenocopies the parent strain and invades into the mucosae. These observations provide an explanation for the distinct phenotypes of SC5314 and highlight the role of heterozygosity as a driver ofC. albicansphenotypic heterogeneity.ImportanceCandida albicansis a commensal fungus that colonizes human oral cavity and gastrointestinal tracts but also causes mucosal as well as invasive disease. The expression of virulence traits inC. albicansclinical isolates is heterogenous and the genetic basis of this heterogeneity is of high interest. TheC. albicansreference strain SC5314 is highly invasive and expresses robust filamentation and biofilm formation relative to many other clinical isolates. Here, we show that SC5314 derivatives are heterozygous for the transcription factor Rob1 and contain an allele with a rare gain-of-function SNP that drives filamentation, biofilm formation, and virulence in a model of oropharyngeal candidiasis. These finding explain, in part, the outlier phenotype of the reference strain and highlight the role of heterozygosity plays in the strain-to-strain variation of diploid fungal pathogens.