Zinc Acquisition: A Key Aspect in Aspergillus fumigatus Virulence

Zinc is an essential micronutrient required for the growth of all microorganisms. To grow in the lungs of a susceptible patient Aspergillus fumigatus must obtain zinc from the surrounding tissues. The concentration of Zn2+ ions in living tissues is much lower than that required for optimal fungal growth in vitro because most of them are tightly bound to proteins at the physiological pH. However, A. fumigatus has several zinc transporters (ZrfA, ZrfB and ZrfC) that enable it to uptake zinc efficiently under the extreme zinc-limiting conditions provided by a susceptible host. The ZafA transcriptional regulator induces the expression of these transporters and is essential for virulence. ZrfC is required for fungal growth within the host tissues, whereas ZrfA and ZrfB play an accessory role. The zinc-scavenging capacity of ZrfC relies on its unusually long N-terminus. In addition, ZrfC also enables A. fumigatus to overcome the inhibitory effect of calprotectin, which is an antimicrobial Zn/Mn-chelating protein synthesized in high amounts by neutrophils, even in immunosuppressed non-leucopenic animals. In summary, the regulation of zinc homeostasis and zinc acquisition could be promising targets for the discovery and development of a new generation of antifungals for the treatment of invasive pulmonary aspergillosis.