The intersection of host and fungus through the zinc lens

Abstract

In this review, we summarize data regarding the influence of zinc on host defenses to human pathogenic fungi and how the fungus acquires zinc to sustain biological functions. Mammals have evolved several extracellular and intracellular mechanisms to withhold zinc from the fungus. Specific immune cells release zinc binding proteins such as calprotectin to capture the metal and deny it to the fungus. Intracellularly, several zinc binding proteins such as metallothioneins starve the fungus of zinc. The net result in both situations is depriving the fungus of a crucial micronutrient. To combat this struggle, fungi have developed means to capture zinc and store it. The mechanisms of transport for various fungi are discussed herein.

1

The many faces of zinc sequestration. A. Neutrophils release calprotectin upon cell death. This molecule binds environmental zinc to sequester it from extracellular pathogens such as Candida and Aspergillus. B. GM-CSF activates macrophages to inhibit intracellular growth of H. capsulatum by enhancing expression of metallothioneins (MTs) 1 and 2 that bind zinc and deprive this metal from phagosomes containing the fungus. C. Interleukin-4 exerts the opposite effect in that it induces expression of MT3. Cathepsins cause detachment of zinc from this metal binding protein. Subsequently, this metal is transported to the phagosome and fortifies H. capsulatum yeast cells survival in phagosomes.

2.

Zinc capture and transport in fungi. Many fungal pathogens encode orthologues of the Candida albicans zincophore zinc scavenger, but the gene has been lost in several important pathogenic species. The zincophore exhibits multiple interaction with host immunity (complement system, neutrophils). In C. albicans, the protease Sap6 additionally delivers zinc. All investigated species encode Zip transporters which can capture zinc from the environment. Internalised zinc is shuttled into organelles (E.R., vacuole, zincosomes) via ZnT transporters which can be subsequently mobilised by intracellular Zip transporters.