Iron in infection and immunity

Abstract

Iron is an essential nutrient for both humans and pathogenic microbes. Because of its ability to exist in one of two oxidation states, iron is an ideal redox catalyst for diverse cellular processes including respiration and DNA replication. However, the redox potential of iron also contributes to its toxicity; thus, iron concentration and distribution must be carefully controlled. Given the absolute requirement for iron by virtually all human pathogens, an important facet of the innate immune system is to limit iron availability to invading microbes in a process termed nutritional immunity. Successful human pathogens must therefore possess mechanisms to circumvent nutritional immunity in order to cause disease. In this review, we discuss regulation of iron metabolism in the setting of infection and delineate strategies used by human pathogens to overcome iron-withholding defenses.

Figure 1. Human iron homeostasis

A) Prior to transport into duodenal enterocytes, dietary ferric iron is reduced by ferric reductases present in the apical brush border. Ferrous iron is transported into the cell by DMT1, after which it can be used for cellular processes, stored in ferritin, or exit the cell via ferroportin (FPN). Extracellular iron is bound with high affinity by transferrin (TF). B) Erythroid precursors acquire iron via transferrin receptor (TFR) – mediated endocytosis of holo-TF, and iron is then transported into the cytoplasm by DMT1. Cytoplasmic iron can subsequently be shuttled to mitochondria for use in heme biosynthesis. C) Macrophages acquire iron via TFR-mediated endocytosis of holo-TF or recycling of senescent erythrocytes. Heme oxygenases catalyze the degradation of heme to iron, CO, and biliverdin, after which iron is transported to the cytoplasm by DMT1. Cytoplasmic iron can be used for cellular processes, stored in ferritin, or transported out of the macrophage by FPN. D) Hemoglobin or heme released upon erythrocyte lysis is avidly scavenged by haptoglobin (HPT) or hemopexin (HPX), respectively.

Figure 2. Iron limitation as an innate immune defense

A) Regulation of hepcidin synthesis during infection and inflammation. B) Pro-inflammatory cytokines fortify iron-withholding defenses via repression of DMT1-mediated iron absorption and activation of ferritin synthesis. Hepcidin induces the internalization and degradation of FPN, further limiting iron egress. C) In response to inflammatory signals, macrophages downregulate the TFR, limiting iron uptake. Iron is actively removed from the phagosome via Nramp1, an activity stimulated by IFN-γ, TNF-α, and IL-1. These actions culminate in reduced iron availability to intracellular pathogens such as Mtb (depicted in red). D) Innate immune effectors further limit iron availability at the infectious focus through local production of lactoferrin (LF), hepcidin, and siderocalin/lipocalin-2 (Lcn2). Pathogens (depicted in green) circumvent iron sequestration through the production of siderophores.

Figure 3. Bacterial strategies for iron acquisition

Bacterial pathogens use a variety of strategies to overcome host iron limitation. Not shown are ferric/ferrous iron transporters and the Borrelia strategy of manganese substitution in metalloenzymes. A) Gram-positive organisms can obtain iron through the use of heme and hemoprotein cell surface receptors, or through secretion of hemophores (B. anthracis). Heme is then shuttled across the cell wall prior to transport into the cytoplasm by ABC-type transporters. Once in the cytoplasm, heme can be degraded by heme oxygenases to release iron. Alternatively, Gram-positive pathogens may secrete siderophores, which capture iron and then re-enter the cell through the use of specific transporters. B) Gram-negative organisms also utilize siderophores and heme/hemoprotein receptors to obtain host iron. Select Gram-negative pathogens express transferrin (TF) or lactoferrin (LF) binding proteins (TBP/LBP) that allow for use of transferrin- or lactoferrin-bound iron. Gram-negative bacteria require energy generated from the TonB/ExbB/ExbD system to enable transport across the outer membrane and periplasm, prior to delivery into the cytoplasm by ABC-type transporters. C) Intracellular pathogens also produce siderophores, which in the case of Mtb (depicted in red) can diffuse out of the phagosome to capture cytoplasmic iron. Additionally, Mtb and other intracellular pathogens can acquire iron from TF as it cycles through the endocytic pathway. Other intracellular pathogens (depicted in green) escape from the phagosome, allowing use of free cytoplasmic iron and ferritin-iron as a nutrient source. Intracellular pathogens may also manipulate host cell iron homeostasis to increase iron availability. For example, Mtb inhibits expression of FPN, effectively increasing intraphagosomal iron content. Furthermore, some intracellular pathogens enhance expression of the transferrin receptor (TFR).