The role of theC. albicanstranscriptional repressorNRG1during filamentation and disseminated candidiasis is strain-dependent

Abstract

Candida albicansis one of the most common causes of superficial and invasive fungal disease in humans. Its ability to cause disease has been closely linked to its ability to undergo a morphological transition from budding yeast to filamentous forms (hyphae and pseudohyphae). The ability ofC. albicansstrains isolated from patients to undergo filamentation varies significantly. In addition, the filamentation phenotypes of mutants involving transcription factors that positively regulate hyphal morphogenesis can also vary from strain to strain. Here, we characterized the virulence, in vitro and in vivo filamentation, and in vitro and in vivo hypha-associated gene expression profiles of four poorly filamentingC. albicansisolates and their corresponding deletion mutants of the repressor of filamentationNRG1. The two most virulent strains, 57055 and 78048, show robust in vivo filamentation while remaining predominately yeast phase exposed to RPMI+10% bovine calf serum at 37°C; the two low virulence strains (94015 and 78042) do not filament well under either condition. Deletion ofNRG1increases hyphae formation in the SC5314 derivative SN250 but only pseudohyphae are formed in the clinical isolates in vivo. Deletion ofNRG1modestly increased the virulence of 78042 which was accompanied by increased expression of hyphae-associated genes without an increase in filamentation. Strikingly, deletion ofNRG1in 78048 reduced filamentation, expression of candidalysin (ECE1) and virulence in vivo without dramatically altering establishment of infection. Thus, the function ofNRG1varies significantly within this set ofC. albicansisolates and can actually suppress filamentation in vivo.ImportanceClinical isolates of the human fungal pathogenCandida albicansshow significant variation in their ability to undergo in vitro filamentation and in the function of well-characterized transcriptional regulators of filamentation. Here, we show that Nrg1, a key repressor of filamentation and filament specific gene expression in standard reference strains, has strain dependent functions, particularly during infection. Most strikingly, loss ofNRG1function can reduce filamentation, hypha-specific gene expression such as the toxin candidalysin, and virulence in some strains. Our data emphasize that the functions of seemingly fundamental and well-conserved transcriptional regulators such as Nrg1 are contextual with respect to both environment and genetic background.