The Lysine Deacetylase RpdA Is Essential for Virulence in Aspergillus fumigatus

Abstract

Current suboptimal treatment options of invasive fungal infections and emerging resistance of the corresponding pathogens urge the need for alternative therapy strategies and require the identification of novel antifungal targets. <i>Aspergillus fumigatus</i> is the most common airborne opportunistic mold pathogen causing invasive and often fatal disease. Establishing a novel <i>in vivo</i> conditional gene expression system, we demonstrate that downregulation of the class 1 lysine deacetylase (KDAC) RpdA leads to avirulence of <i>A. fumigatus</i> in a murine model for pulmonary aspergillosis. The <i>xylP</i> promoter used has previously been shown to allow xylose-induced gene expression in different molds. Here, we demonstrate for the first time that this promoter also allows <i>in vivo</i> tuning of <i>A. fumigatus</i> gene activity by supplying xylose in the drinking water of mice. In the absence of xylose, an <i>A. fumigatus</i> strain expressing <i>rpdA</i> under control of the <i>xylP</i> promoter, <i>rpdA</i> ^<i>xylP</i> , was avirulent and lung histology showed significantly less fungal growth. With xylose, however, <i>rpdA</i> ^<i>xylP</i> displayed full virulence demonstrating that xylose was taken up by the mouse, transported to the site of fungal infection and caused <i>rpdA</i> induction <i>in vivo</i>. These results demonstrate that (i) RpdA is a promising target for novel antifungal therapies and (ii) the <i>xylP</i> expression system is a powerful new tool for <i>in vivo</i> gene silencing in <i>A. fumigatus</i>.