Iron homeostasis--Achilles' heel of Aspergillus fumigatus?

Abstract

The opportunistic fungal pathogen Aspergillus fumigatus adapts to iron limitation by upregulation of iron uptake mechanisms including siderophore biosynthesis and downregulation of iron-consuming pathways to spare iron. These metabolic changes depend mainly on the transcription factor HapX. Consistent with the crucial role of iron in pathophysiology, genetic inactivation of either HapX or the siderophore system attenuates virulence of A. fumigatus in a murine model of aspergillosis. The differences in iron handling between mammals and fungi might serve to improve therapy and diagnosis of fungal infections.

Figure 1

A. fumigatusmechanisms for iron uptake and storage. (a) Schematic summary of iron uptake and storage mechanisms. (b) Siderophore structures. R = H in FsC and R = acetyl in TAFC; the hydroxylation site in FC is unknown. (c) Siderophore biosynthetic pathway. See text for details.

Figure 2

Iron regulation inA. fumigatus.

Figure 3

PET imaging of invasive pulmonary aspergillosis in a rat model using⁶⁸Ga-TAFC. Images demonstrating accumulation of ⁶⁸Ga in infected lungs were taken one hour after injection of ⁶⁸Ga-TAFC into the femoral vein. Kidneys are labeled in infected and non-infected animals owing to renal excretion of ⁶⁸Ga-TAFC. This figure was reprinted by permission of the Society of Nuclear Medicine from [51^•].