Abstract
In response to temperature, Blastomyces dermatitidis converts between yeast and mold forms. Knowledge of the mechanism(s) underlying this response to temperature remains limited. In B. dermatitidis, we identified a GATA transcription factor, SREB, important for the transition to mold. Null mutants (SREBΔ) fail to fully complete the conversion to mold and cannot properly regulate siderophore biosynthesis. To capture the transcriptional response regulated by SREB early in the phase transition (0–48 hours), gene expression microarrays were used to compare SREB∆ to an isogenic wild type isolate. Analysis of the time course microarray data demonstrated SREB functioned as a transcriptional regulator at 37°C and 22°C. Bioinformatic and biochemical analyses indicated SREB was involved in diverse biological processes including iron homeostasis, biosynthesis of triacylglycerol and ergosterol, and lipid droplet formation. Integration of microarray data, bioinformatics, and chromatin immunoprecipitation identified a subset of genes directly bound and regulated by SREB in vivo in yeast (37°C) and during the phase transition to mold (22°C). This included genes involved with siderophore biosynthesis and uptake, iron homeostasis, and genes unrelated to iron assimilation. Functional analysis suggested that lipid droplets were actively metabolized during the phase transition and lipid metabolism may contribute to filamentous growth at 22°C. Chromatin immunoprecipitation, RNA interference, and overexpression analyses suggested that SREB was in a negative regulatory circuit with the bZIP transcription factor encoded by HAPX. Both SREB and HAPX affected morphogenesis at 22°C; however, large changes in transcript abundance by gene deletion for SREB or strong overexpression for HAPX were required to alter the phase transition.
Highlights
Blastomyces dermatitidis belongs to a group of medically important ascomycetes that adapt to shifts in temperature by undergoing a morphologic switch known as the phase transition [1]
Blastomyces dermatitidis belongs to a group of human pathogenic fungi that convert between two forms, mold and yeast, in response to temperature
We identified SREB, a transcription factor that regulates disparate processes including dimorphism
Summary
Blastomyces dermatitidis belongs to a group of medically important ascomycetes that adapt to shifts in temperature by undergoing a morphologic switch known as the phase transition [1]. Following soil disruption, aerosolized conidia and mold fragments inhaled into the lungs of a mammalian host (37°C) convert into pathogenic yeast [1,2]. In the yeast form, B. dermatitidis is able to evade host immune defenses to cause pneumonia and disseminate to other organs such as the bone or brain [3,4,5]. This adaptive response, which is essential for virulence [2], is conserved in Histoplasma capsulatum, Coccidioides immitis, Coccidioides posadasii, Paracoccidioides brasiliensis, Penicillium marneffei, and Sporothrix schenckii [1]. The transition in the opposite direction, yeast to mold, is postulated to facilitate survival outside the mammalian host, sexual reproduction by mating, and geographic dispersion through production of conidia [6]
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