Copper Homeostasis in Aspergillus fumigatus: Opportunities for Therapeutic Development

Abstract

Aspergillus fumigatus can cause severe invasive aspergillosis in immunocompromised individuals. Copper, an essential but potentially toxic trace element for A. fumigatus, plays a critical role at the host-pathogen axis during infection. Accumulating evidence demonstrates that the host utilizes copper compartmentalization within macrophages to combat A. fumigatus infection. To survive under host-imposed copper toxicity, A. fumigatus has evolved sophisticated machinery to regulate copper homeostasis. Thus, targeting molecular pathways critical for copper homeostasis regulation provides an opportunity to improve therapeutic options for aspergillosis caused by A. fumigatus. In this review, we describe the copper homeostatic mechanisms by which A. fumigatus acquires and controls copper levels and explores the responses of the pathogen to alter copper levels in the host. Finally, we discuss the regulatory mechanisms of copper homeostasis that could be targeted for antifungal drug development.

Keywords: Aspergillus fumigatus; antifungal therapeutic target; copper homeostasis; copper transcription factor; copper transporters.

Figure 1

Copper homeostasis mechanisms in A. fumigatus. ① High-affinity copper transporters at the plasma membrane participate in copper (blue spheres) transport from the extracellular environment to the intracellular environment. ② In the cytoplasm, copper is bound by copper chaperones that facilitate the delivery of copper to the nucleus for copper homeostasis regulation; AfMac1 induces the ctrC and ctrA2 genes to respond to low copper, and AfAceA induces the expression of the copper extrusion pump CrpA, as well as the ROS detoxification proteins AtfA and SOD1, in response to excess copper. ③ In the cytoplasm, copper is bound by copper chaperones that facilitate the delivery of copper to subcellular compartments (i.e., the Golgi complex) for storage or ④⑤ cytoplasmic and mitochondrial enzymes for functional activation. Parts 3, 4, and 5 are not proven in A. fumigatus, only in S. cerevisiae. ⑥ When the concentration of copper in the cytoplasm exceeds the homeostatic capacity, A. fumigatus employs efflux to detoxify excess copper. Abbreviations: SOD, superoxide dismutase; ROS, reactive oxygen species.

Figure 2

A. fumigatus response to host-imposed copper toxicity. Macrophages encountering A. fumigatus react by upregulating the host copper (purple spheres) transporter Ctr1 and aggregating ATP7A at the phagolysosomal membrane to facilitate copper uptake. A. fumigatus AfAceA utilizes the copper exporter CrpA and the ROS-responsive transcription factor AtfA to respond to host-imposed copper toxicity.