Shared and distinct mechanisms of iron acquisition by bacterial and fungal pathogens of humans

Abstract

Iron is the most abundant transition metal in the human body and its bioavailability is stringently controlled. In particular, iron is tightly bound to host proteins such as transferrin to maintain homeostasis, to limit potential damage caused by iron toxicity under physiological conditions and to restrict access by pathogens. Therefore, iron acquisition during infection of a human host is a challenge that must be surmounted by every successful pathogenic microorganism. Iron is essential for bacterial and fungal physiological processes such as DNA replication, transcription, metabolism, and energy generation via respiration. Hence, pathogenic bacteria and fungi have developed sophisticated strategies to gain access to iron from host sources. Indeed, siderophore production and transport, iron acquisition from heme and host iron-containing proteins such as hemoglobin and transferrin, and reduction of ferric to ferrous iron with subsequent transport are all strategies found in bacterial and fungal pathogens of humans. This review focuses on a comparison of these strategies between bacterial and fungal pathogens in the context of virulence and the iron limitation that occurs in the human body as a mechanism of innate nutritional defense.

Keywords: heme; hemoglobin; iron; microbial pathogenesis; siderophores; transferrin.

Figure 1

Iron transport and homeostasis in human cells. (A) Iron recycling in macrophages via phagocytosis of senescent red blood cells, uptake of heme-hemopexin and hemoglobin-haptoglobin complexes, and iron-loaded transferrin. (B) Dietary iron and heme absorption by intestinal endocytes via DMT1 and the heme receptor HCP1/FLVCR2, respectively. Iron-loaded siderocalin can also be absorbed via the receptor 24p3R. Iron is extracted from these carriers by heme oxygenase in lysosomes or by reductases in endosomes and is used for metabolic processes (mitochondria, storage, or export). Export is performed by ferroportin in partnership with ceruloplasmin in macrophages and with hephaestin in intestinal cells. Iron is loaded on transferrin for distribution. The descriptions of the specific proteins are given in the text.

Figure 2

Diagrams of hemoglobin and heme uptake and utilization. Mechanisms are depicted for the Gram-negative bacterium Pseudomonas aeruginosa via the Phu system, and for the Gram-positive bacterium Staphylococcus aureus via the Isd system. For comparison, the scheme in the fungal pathogen Candida albicans is also illustrated and components include the receptors Rbt5, Rbt51, and Pga7. A schematic is also included to depict endocytosis (via ESCRT functions) and processing (with the heme oxygenase Hmx1). Additional details about the specific proteins are given in the text.

Figure 3

Iron acquisition from transferrin and lactoferrin. Mechanisms are shown for the Gram-negative bacterium Neisseria gonorrhoeae through the TbpAB-FbpABC transporter, and for the Gram-positive bacterium Staphylococcus aureus via the SstABCD transporter and catecholamines. For comparison, the uptake of iron that is potentially released from transferrin by the activity of the reductase Fre10 and the permease Ftr1 is also shown for the pathogenic fungus Candida albicans. The ferroxidase that functions with Ftr1 is not depicted. The descriptions of the specific proteins are given in the text.

Figure 4

Schemes for ferric iron uptake via siderophores. The receptor IroN, the ABC-transporter FepBCDG and the esterases Fes, IroD, and IroE mediate the uptake of iron-loaded enterobactin and salmochelins in the Gram-negative bacterium Escherichia coli. For Staphylococcus aureus, the ABC transporters HstABC and SirABC perform the uptake of the siderophores staphyloferrin A and staphyloferrin B, respectively. The fungus Aspergillus fumigatus secretes the siderophores FsC and TAFC, and the major facilitator superfamily protein MirB is known to transport TAFC for subsequent degradation by the EstB. The descriptions of the specific proteins are given in the text.

Figure 5

Schemes for ferrous iron uptake. The Gram-negative bacterium Yersinia pestis uses the YfeABCD proteins and the Gram-positive bacterium Bacillus subtilis uses the EfeUOB complex to accomplish ferrous iron uptake. A comparable process is shown for the fungal pathogen Cryptococcus neoformans. This pathogen used the Cfo1-Cft1 multicopper oxidase-iron permease complex, the cell wall pigment melanin, and the secreted reductant 3-hydroxyanthranilic acid to perform reduction and ferrous iron uptake. Note that ferrous iron is oxidized by Cfo1 prior to transport into the cell by Cft1. Physiological evidence for an additional low affinity transport system for ferrous iron has been presented for C. neoformans and this is indicated by a question mark (Jacobson et al., 1998). Additional details for each system are provided in the text.