Sterol Regulatory Element Binding Protein (Srb1) Is Required for Hypoxic Adaptation and Virulence in the Dimorphic Fungus <i>Histoplasma capsulatum</i>


<div><p>The <i>Histoplasma capsulatum</i> sterol regulatory element binding protein (SREBP), Srb1 is a member of the basic helix-loop-helix (bHLH), leucine zipper DNA binding protein family of transcription factors that possess a unique tyrosine (Y) residue instead of an arginine (R) residue in the bHLH region. We have determined that <i>Srb1</i> message levels increase in a time dependent manner during growth under oxygen deprivation (hypoxia). To further understand the role of Srb1 during infection and hypoxia, we silenced the gene encoding Srb1 using RNA interference (RNAi); characterized the resulting phenotype, determined its response to hypoxia, and its ability to cause disease within an infected host. Silencing of <i>Srb1</i> resulted in a strain of <i>H</i>. <i>capsulatum</i> that is incapable of surviving <i>in vitro</i> hypoxia. We found that without complete <i>Srb1</i> expression, <i>H</i>. <i>capsulatum</i> is killed by murine macrophages and avirulent in mice given a lethal dose of yeasts. Additionally, silencing <i>Srb1</i> inhibited the hypoxic upregulation of other known <i>H</i>. <i>capsulatum</i> hypoxia-responsive genes (HRG), and genes that encode ergosterol biosynthetic enzymes. Consistent with these regulatory functions, <i>Srb1</i> silenced <i>H</i>. <i>capsulatum</i> cells were hypersensitive to the antifungal azole drug itraconazole. These data support the theory that the <i>H</i>. <i>capsulatum</i> SREBP is critical for hypoxic adaptation and is required for <i>H</i>. <i>capsulatum</i> virulence.</p></div

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oai:figshare.com:article/3999870Last time updated on 2/12/2018

This paper was published in FigShare.

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