Candida albicans Sfl2, a temperature-induced transcriptional regulator, is required for virulence in a murine gastrointestinal infection model

Abstract

Many transcriptional regulators play roles in morphogenesis of the human pathogen Candida albicans. Recently, Sfl2, a sequence homolog of C. albicans Sfl1, has been shown to be required for hyphal development. In this report, we show that, like Sfl1, Sfl2 could complement the phenotypes of the Saccharomyces cerevisiae sfl1 mutant, and green fluorescent protein-tagged Sfl2 localized in the nuclei of both yeast and hyphal cells in C. albicans, reflecting its role as a transcriptional regulator. In C. albicans, SFL2 expression was induced at a high growth temperature (37 °C) at both transcriptional and translational levels. The deletion of SFL2 impaired filamentation at a high temperature, whereas the overexpression of SFL2 promoted filamentous growth at a low temperature. Sfl2-activated hyphal development needs the existence of Efg1 and Flo8 under aerobic conditions. Thus, in contrast to Sfl1, which represses filamentation, Sfl2 acts as an activator of filamentous growth in C. albicans. Functional analysis of chimeric Sfl proteins demonstrated that the opposite actions of C. albicans Sfl1 and Sfl2 were mainly mediated by their heat shock factor domains. Furthermore, the deletion of SFL2 attenuated virulence in a mouse model of gastrointestinal colonization and dissemination, indicating that Sfl2 is important for virulence in the gastrointestinal model of candidiasis. Our results provide new insights into Sfl2 functions in C. albicans morphogenesis and pathogenesis.

A comprehensive functional portrait of two heat shock factor-type transcriptional regulators involved in Candida albicans morphogenesis and virulence

“…On the other hand, we and others have shown that deletion of SFL2 impaired filamentation in response to different cues, whereas SFL2 overexpression promoted hyphal growth, even under non hyphae-stimulating conditions [39][40][41]. Noteworthy, an sfl2D/ sfl2D strain exhibited reduced damage in a reconstituted human oral epithelium model and displayed attenuated virulence in a mouse model of gastrointestinal colonization and dissemination model [39,40], indicating that Sfl2p also plays an important role in C. albicans pathogenesis. Similar to Sfl1p, an Sfl2p-GFP fusion localized to the nucleus, in line with a role in transcriptional regulation [39].…”

“…Noteworthy, an sfl2D/ sfl2D strain exhibited reduced damage in a reconstituted human oral epithelium model and displayed attenuated virulence in a mouse model of gastrointestinal colonization and dissemination model [39,40], indicating that Sfl2p also plays an important role in C. albicans pathogenesis. Similar to Sfl1p, an Sfl2p-GFP fusion localized to the nucleus, in line with a role in transcriptional regulation [39].…”

“…Interestingly, the C. albicans genome encodes two structural homologs of ScSfl1p, namely Sfl1p and Sfl2p [37][38][39][40]. Either SFL1 or SFL2 functionally complement an S. cerevisiae sfl1 mutation [38,39] and encode important regulators of morphogenesis and virulence in C. albicans [37][38][39][40]. Intriguingly, although sharing structural homologies, Sfl1p and Sfl2p have antagonistic functions: while Sfl1p acts as a negative regulator of hyphal development, Sfl2p acts as a positive regulator of this process [37][38][39][40].…”

“…ScSfl1p has dual activator/repressor functions, acting as a transcriptional repressor of flocculation-related genes and as an activator of stress-responsive genes [35,36]. Interestingly, the C. albicans genome encodes two structural homologs of ScSfl1p, namely Sfl1p and Sfl2p [37][38][39][40]. Either SFL1 or SFL2 functionally complement an S. cerevisiae sfl1 mutation [38,39] and encode important regulators of morphogenesis and virulence in C. albicans [37][38][39][40].…”

“…Either SFL1 or SFL2 functionally complement an S. cerevisiae sfl1 mutation [38,39] and encode important regulators of morphogenesis and virulence in C. albicans [37][38][39][40]. Intriguingly, although sharing structural homologies, Sfl1p and Sfl2p have antagonistic functions: while Sfl1p acts as a negative regulator of hyphal development, Sfl2p acts as a positive regulator of this process [37][38][39][40]. Functional analyses of C. albicans Sfl1p showed that deletion of SFL1 promoted filamentous growth and cell flocculation and correlated with induction of HSGs (ECE1, HWP1) and genes involved in cell adhesion (ALS1, ALS3), whereas its overexpression inhibited hyphal formation [37,38].…”