The mitochondrial thiamine pyrophosphate transporter TptA promotes adaptation to low iron conditions and virulence in fungal pathogen <i>Aspergillus fumigatus</i>

<i>Aspergillus fumigatus</i> is the most prevalent airborne fungal pathogen that causes invasive fungal infections in immunosuppressed individuals. Adaptation to iron limited conditions is crucial for <i>A. fumigatus</i> virulence. To identify novel genes that play roles in adaptation to low iron conditions we performed an insertional mutagenesis screen in <i>A. fumigatus</i>. Using this approach, we identified the <i>tptA</i> gene in <i>A. fumigatus</i>, which shares homology with the <i>Saccharomyces cerevisiae</i> thiamine pyrophosphate (ThPP) transporter encoding gene <i>tpc1</i>. Heterologous expression of <i>tpc1</i> in the <i>tptA</i> deletion mutant completely restored the ThPP auxotrophy phenotype, suggesting that Tpc1 and TptA are functional orthologues. Importantly, TptA was required for adaptation to low iron conditions in <i>A. fumigatus</i>. The <i>ΔtptA</i> mutant had decreased resistance to the iron chelator bathophenanthroline disulfonate (BPS) with severe growth defects. Moreover, loss of <i>tptA</i> decreased the expression of <i>hapX</i>, which is a major transcription factor indispensable for adaptation to iron starvation in <i>A. fumigatus</i>. Overexpression of <i>hapX</i> in the <i>ΔtptA</i> strain greatly rescued the growth defect and siderophore production by <i>A. fumigatus</i> in iron-depleted conditions. Mutagenesis experiments demonstrated that the conserved residues related to ThPP uptake in TptA were also required for low iron adaptation. Furthermore, TptA-mediated adaptation to low iron conditions was found to be dependent on carbon sources. Finally, loss of <i>tptA</i> resulted in the attenuation of virulence in a murine model of aspergillosis. Taken together, this study demonstrated that the mitochondrial ThPP transporter TptA promotes low iron adaptation and virulence in <i>A. fumigatus</i>.