Two negative regulators of biofilm development exhibit functional divergence in conferring virulence potential toCandida albicans

Abstract

Candida albicans, a human pathogen, carries an expanded family of Zn(II)2Cys6 transcription factors. A CTG clade-specific protein Zcf32 and its closely related protein Upc2, a well-conserved transcription factor across the various fungal species, belong to this family of proteins. Unlike Upc2, Zcf32 is poorly studied in C. albicans. Here, we examined roles played by these two related transcription factors in biofilm development and virulence of C. albicans. Our data show that the null mutants of each of Zcf32 or Upc2 form better biofilms than the wild-type suggesting that both of them negatively regulate the biofilm development. While acting as negative regulators of biofilm formation, these two transcription factors target a different set of biofilm genes. A mouse model of candidiasis reveals that zcf32/zcf32 was hypervirulent while upc2/upc2 shows compromised virulence compared to the wild-type. Notably, the absence of Zcf32 enhances detrimental inflammation brought about by TNFα, IFNβ, and IFNγ. upc2/upc2 failed to generate a similar feedback, instead demonstrated an elevated anti-inflammatory (IL4 and IL10) host response. Taking together, we show how a recently evolved transcription factor Zcf32 retained functional resemblance with a more ubiquitous member Upc2 but also functionally diverged from the latter in the regulation of biofilm development and virulence of the pathogen.

Transcriptional Circuits Regulating Developmental Processes in Candida albicans

“…As such, several of the 50 auxiliary transcriptional regulators are integrated into the larger biofilm network that includes the core nine transcriptional regulators and all of their directly bound target genes (Nobile et al, 2012). Based on existing phenotypic analyses of the mutant strains of the auxiliary biofilm transcriptional regulators, the majority (48) are implicated in the regulation of adhesion and/or filamentation (Brown et al, 1999;Kadosh and Johnson, 2001;Cheng et al, 2003;Uhl et al, 2003;Garcıá-Sańchez et al, 2004;Kelly et al, 2004;Mulhern et al, 2006;Kim et al, 2008b;Shen et al, 2008;Wheeler et al, 2008;Homann et al, 2009;Nobile et al, 2009;Pukkila-Worley et al, 2009;Uppuluri et al, 2010a;Uppuluri et al, 2010b;Askew et al, 2011;Bonhomme et al, 2011;Ganguly et al, 2011;Finkel et al, 2012;Kamthan et al, 2012;Langford et al, 2013;Delgado-Silva et al, 2014;Tsai et al, 2014;Chen and Lan, 2015;Fox et al, 2015;Ghosh et al, 2015;Kakade et al, 2016;Kakade et al, 2019;Böttcher et al, 2020;Lagree et al, 2020;Omran et al, 2020;Wang et al, 2020); 16 are implicated in drug resistance and/or tolerance (Bruno et al, 2006;Cornet et al, 2006;Mulhern et al, 2006;Xu et al, 2007;…”

The histone chaperone HIR maintains chromatin states to control nitrogen assimilation and fungal virulence

“…Moreover, in vivo hypervirulence phenotypes of C. albicans deletion mutants have been rarely observed until today. The Candida Genome Database (CGD) lists some 506 unique genes whose genetic ablation is associated with decreased/absent/delayed virulence in various model systems, while only 11 unique genes are linked to hypervirulence phenotypes (for recent reports, see Bahnan et al, 2012 ; Day et al, 2017 ; Kakade et al, 2019 ; Soloviev et al, 2011 ; Tams et al, 2019 ). Hence, our study serves as a basis to uncover yet-ill-defined aspects of chromatin biology in fungal pathophysiology, antifungal treatment strategies, and mechanisms of immune evasion.…”

Metabolic reprogramming during Candida albicans planktonic-biofilm transition is modulated by the transcription factors Zcf15 and Zcf26

“…Yet, it is notable that most modulators in the regulation of C. albicans biofilm formation identified so far are positive regulators. Only a few transcription regulators such as Nrg1, Zcf32, and Upc2 have been shown to play a negative role during C. albicans biofilm formation [18,24,25]. This may be a consequence of the approach used to identify these modulators, as the biofilm growth conditions did not allow an increase in biofilm biomass to be observed when the target genes were inactivated, as expected for genes encoding negative regulators of biofilm formation [18].…”