The Iron Tug-of-War between Bacterial Siderophores and Innate Immunity

Abstract

Iron is necessary for the survival of almost all aerobic organisms. In the mammalian host, iron is a required cofactor for the assembly of functional iron-sulfur (Fe-S) cluster proteins, heme-binding proteins and ribonucleotide reductases that regulate various functions, including heme synthesis, oxygen transport and DNA synthesis. However, the bioavailability of iron is low due to its insolubility under aerobic conditions. Moreover, the host coordinates a nutritional immune response to restrict the accessibility of iron against potential pathogens. To counter nutritional immunity, most commensal and pathogenic bacteria synthesize and secrete small iron chelators termed siderophores. Siderophores have potent affinity for iron, which allows them to seize the essential metal from the host iron-binding proteins. To safeguard against iron thievery, the host relies upon the innate immune protein, lipocalin 2 (Lcn2), which could sequester catecholate-type siderophores and thus impede bacterial growth. However, certain bacteria are capable of outmaneuvering the host by either producing "stealth" siderophores or by expressing competitive antagonists that bind Lcn2 in lieu of siderophores. In this review, we summarize the mechanisms underlying the complex iron tug-of-war between host and bacteria with an emphasis on how host innate immunity responds to siderophores.

Keywords: Dihydroxybenzoic acid; Enterochelin; NGAL; Siderocalin.

Fig. 1

Siderophore structures. a The bacterial catecholate siderophore structures of Ent, Bcb, Ptb and Vbb. b The structures for the bacterial hydroxamate siderophores, DFO and exochelin. c Diagrams of the mixed siderophores, including aerobactin (citryl-hydroxamate), yersiniabactin (phenolate/thiazoline), pyoverdine (catecholate-hydroxamate), pyochelin (phenol-catecholate), mycobactin (hydroxyphenyloxazoline derived from salicylic acid), and carboxymycobactin (carboxylate of mycobactin). d The proposed mammalian siderophores 2,5-DHBA and norepinephrine. These are suggested siderophores due to their structural similarities with 2,3-DHBA of Ent.

Fig. 2

Iron tug-of-war: how Lcn2 and MPO interact with siderophores. MPO is secreted from the primary granules (1⁰) of neutrophils and utilizes hydrogen peroxide and halide ions to form hypochlorous acid (HOCl) that serves as an oxidizing and antimicrobial agent. Apo-Ent inhibits full activation of MPO, thus blunting HOCl production; moreover, apo-Ent also prevents the degranulation of MPO and formation of NETs. A second mechanism to thwart siderophores is by secreting Lcn2 from the secondary granules (2⁰) of neutrophils, where Lcn2 binds to holo- or apo-Ent in a 1: 1 ratio. However, some pathogens have evolved stealth siderophores that are insensitive to Lcn2 and thus can supply iron to pathogens.