Induction of theCandida albicansFilamentous Growth Program by Relief of Transcriptional Repression: A Genome-wide Analysis

Abstract

Candida albicans, the major human fungal pathogen, undergoes a reversible morphological transition from blastospores (round budding cells) to filaments (elongated cells attached end-to-end). This transition, which is induced upon exposure of C. albicans cells to a number of host conditions, including serum and body temperature (37°C), is required for virulence. Using whole-genome DNA microarray analysis, we describe 61 genes that are significantly induced (>2-fold) during the blastospore to filament transition that takes place in response to exposure to serum and 37°C. We next show that approximately half of these genes are transcriptionally repressed in the blastospore state by three transcriptional repressors, Rfg1, Nrg1, and Tup1. We conclude that the relief of this transcriptional repression plays a key role in bringing the C. albicans filamentous growth program into play, and we describe the framework of this transcriptional circuit. INTRODUCTIONThe yeast Candida albicans is the major human fungal pathogen. Although normally present as a commensal organism in the human digestive tract, Candida can cause oral and vaginal thrush, as well as a variety of more serious mucosal and systemic infections. Unlike most pathogens, Candida is capable of infecting all the major organs and tissues of the human body and has no known reservoir outside of warmblooded animals (Odds, 1988(Odds, , 1994a(Odds, , 1994bDupont, 1995;Weig et al., 1998). Candidiasis is now the fourth-leading cause of hospital-acquired infections in the world with an attributable mortality of up to 35% (Edmond et al., 1999). Immunocompromised individuals, such as cancer patients undergoing chemotherapy, AIDS patients, and organ transplant recipients are particularly susceptible to Candida infections (for reviews see Shepherd et al., 1985;Dupont, 1995;Weig et al., 1998). Currently, approximately $1 billion per year is spent on the treatment of patients with hospitalacquired infections in the United States alone (Miller et al., 2001).Several properties of C. albicans are known to contribute to its virulence. These include adhesiveness to host cells, secretion of degradative enzymes, and-the subject of this article-the ability to undergo a reversible morphological transition from the blastospore (single-celled) to filamentous (elongated cells attached end-to-end) forms (Lo et al., 1997;Mitchell, 1998;Brown and Gow, 1999;Ernst, 2000aErnst, , 2000bCalderone and Fonzi, 2001;Brown, 2002b;Calderone and Gow, 2002;Saville et al., 2003). The filamentous forms of C. albicans encompass two distinct morphologies, pseudohyphae and hyphae. In pseudohyphae, the cells are attached end-to-end but each cell has an elliptical shape with constrictions at the septa. In true hyphae, these constrictions are absent and a row of cells show a relatively uniform width. Pseudohyphae and hyphae also differ in other respects, including the precise ways that mitosis and cell division are carried out (Odds, 1985(Odds, , 1988Sudbery et al., 2004). In this article, we use the term filam...

Chemical screening identifies filastatin, a small molecule inhibitor of Candida albicans adhesion, morphogenesis, and pathogenesis

“…4E) and mediated by a complex transcriptional network (8,24). In addition to nutrient-poor Spider media, mammalian serum also induces hyphae (25,26), and we observed that filastatin inhibited the response to both these stimuli (Fig. 3B).…”

Efg1-mediated Recruitment of NuA4 to Promoters Is Required for Hypha-specific Swi/Snf Binding and Activation inCandida albicans

“…Flo8 is a potential cofactor of Efg1 at the promoters of hypha-specific genes as the two regulators interact with each other and share a common set of target genes . Negative regulators of the hyphal-specific transcription, such as Nrg1 and Sfl1 (Braun et al, 2001;Murad et al, 2001;Garcia-Sanchez et al, 2005;Kadosh and Johnson, 2005;Bauer and Wendland, 2007;Li et al, 2007), are also potential candidates that can function to repress the transcription during yeast growth by keeping H4 acetylation levels low. Future experiments need to address the identity and mechanisms of how these regulators are induced in response to extracellular stimuli and regulate hypha-specific nucleosomal H4 acetylation.…”

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

“…These transcription factors include (among others) Efg1p/ Flo8p, acting downstream of cAMP-PKA [14][15][16][17][18][19][20], Tec1p [21] and Ume6p [22,23]. Hyphal morphogenesis is also subject to negative regulation mostly by the general corepressor Tup1p through interaction with the transcriptional repressors Nrg1p and Rfg1p [4,12,[24][25][26][27].…”