Essential metals at the host-pathogen interface: nutritional immunity and micronutrient assimilation by human fungal pathogens

Abstract

The ability of pathogenic microorganisms to assimilate sufficient nutrients for growth within their hosts is a fundamental requirement for pathogenicity. However, certain trace nutrients, including iron, zinc and manganese, are actively withheld from invading pathogens in a process called nutritional immunity. Therefore, successful pathogenic species must have evolved specialized mechanisms in order to adapt to the nutritionally restrictive environment of the host and cause disease. In this review, we discuss recent advances which have been made in our understanding of fungal iron and zinc acquisition strategies and nutritional immunity against fungal infections, and explore the mechanisms of micronutrient uptake by human pathogenic fungi.

Keywords: fungal pathogenicity; host–pathogen interactions; iron; zinc.

Graphical Abstract Figure.

The human body tightly sequesters essential micronutrients, restricting their access to invading microorganisms, and pathogenic species must counteract this action of ‘nutritional immunity’.

Figure 1.

Model of haem/haemoglobin iron utilization by C. albicans. Erythrocytes are bound and lysed by C. albicans hyphae by as-yet unknown molecular mechanisms (inset). Released haem/haemoglobin is bound at the outer surface of the cell wall by members of the Rbt5 family and in the surrounding environment by the secreted Csa2. Haem is shuttled through the cell wall via an Rbt5-Pga7 relay network and endocytosed, before being metabolized in the vacuole by the haem oxygenase, Hmx1.

Figure 2.

Model of ferritin and siderophore utilization by C. albicans. Ferritin is bound by Als3 at the hyphal cell surface. Local acidification releases ferric (Fe³⁺) iron which is reduced to ferrous (Fe²⁺) iron by the action of a family of ferric reductases (e.g. Fre10). Ferrous iron is subsequently reoxidized to ferric iron via multicopper oxidase activity (Fet3). Ferric iron is transported into the cell via the high-affinity permease, Ftr1. Candida albicans assimilates xenosiderophores (siderophores produced by other species) via the siderophore transporter, Sit1/Arn1.

Figure 3.

Model of the antifungal activity of neutrophil extracellular traps and calprotectin. Neutrophils sense the larger physical dimensions of pathogens such as C. albicans hyphae and undergo NETosis. The high levels of calprotectin decorating the NETs elicit local zinc depletion against the fungus (inset, top left). Viable neutrophils target the fungus with ROS; C. albicans counterattacks with expression of the copper-only superoxide dismutase, Sod5 (inset, bottom right).

Figure 4.

Zinc manipulation in activated H. capsulatum-containing macrophages. Activation of macrophages via GM-CSF results in STAT3/5-dependent upregulation of metallothioneins (MT), which bind zinc. Zinc is further sequestered away from phagocytosed yeast cells via the action of the ZnT-type zinc transporters, ZnT4 and ZnT7. Total cellular zinc is elevated via ZIP2. These events are associated with an enhanced oxidative burst.

Figure 5.

Model of zinc homeostasis in the model yeast, S. cerevisiae. The zinc-responsive transcription factor Zap1 responds to diminishing metal levels by triggering expression of the zinc importers, Zrt1 and Zrt2, and the vacuolar zinc exporter, Zrt3. In the presence of elevated zinc, the metal is efficiently detoxified in the fungal vacuole via Zrc1 and Cot1.