Uptake of the Siderophore Triacetylfusarinine C, but Not Fusarinine C, Is Crucial for Virulence of Aspergillus fumigatus

Abstract

ABSTRACT Siderophores play an important role in fungal virulence, serving as trackers for in vivo imaging and as biomarkers of fungal infections. However, siderophore uptake is only partially characterized. As the major cause of aspergillosis, Aspergillus fumigatus is one of the most common airborne fungal pathogens of humans. Here, we demonstrate that this mold species mediates the uptake of iron chelated by the secreted siderophores triacetylfusarinine C (TAFC) and fusarinine C by the major facilitator-type transporters MirB and MirD, respectively. In a murine aspergillosis model, MirB but not MirD was found to be crucial for virulence, indicating that TAFC-mediated uptake plays a dominant role during infection. In the absence of MirB, TAFC becomes inhibitory by decreasing iron availability because the mutant is not able to recognize iron that is chelated by TAFC. MirB-mediated transport was found to tolerate the conjugation of fluorescein isothiocyanate to triacetylfusarinine C, which might aid in the development of siderophore-based antifungals in a Trojan horse approach, particularly as the role of MirB in pathogenicity restrains its mutational inactivation. Taken together, this study identified the first eukaryotic siderophore transporter that is crucial for virulence and elucidated its translational potential as well as its evolutionary conservation. IMPORTANCE Aspergillus fumigatus is responsible for thousands of cases of invasive fungal disease annually. For iron uptake, A. fumigatus secretes so-called siderophores, which are taken up after the binding of environmental iron. Moreover, A. fumigatus can utilize siderophore types that are produced by other fungi or bacteria. Fungal siderophores raised considerable interest due to their role in virulence and their potential for the diagnosis and treatment of fungal infections. Here, we demonstrate that the siderophore transporter MirB is crucial for the virulence of A. fumigatus, which reveals that its substrate, triacetylfusarinine C, is the most important siderophore during infection. We found that in the absence of MirB, TAFC becomes inhibitory by decreasing the availability of environmental iron and that MirB-mediated transport tolerates the derivatization of its substrate, which might aid in the development of siderophore-based antifungals. This study significantly improved the understanding of fungal iron homeostasis and the role of siderophores in interactions with the host.

Keywords

• fungi
• molds
• Aspergillus fumigatus
• iron
• siderophore
• uptake