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.

An atlas of cell types in the mammalian epididymis and vas deferens

“…The aldo-keto reductases may also protect sperm from oxidative damage during transfer outside the body. The lipocalins are a family of small molecule binding proteins which bind to lipophilic cargoes with a range of functions from signaling (retinoic acid, (Lareyre et al, 1998; Ong et al, 2000)) to innate immunity (siderophores, (Golonka et al, 2019)). Serine protease inhibitors are homologous to the semen coagulum proteins (which are synthesized primarily by the seminal vesicle) and potentially play some role in the protease-controlled processes of semen coagulation and liquefaction (Clauss et al, 2011), but may also be involved in acrosome maturation and sperm capacitation (Ma et al, 2013).…”

Scavenging Bacterial Siderophores with Engineered Lipocalin Proteins as an Alternative Antimicrobial Strategy

“…In human plasma, for example, the concentration of free Fe III is only about 10 −24 m , essentially due to the complexation by transferrin . However, to ensure an iron supply, microbes have evolved an elaborate strategy: They secrete so‐called siderophores, small organic molecules that chelate Fe III with extremely high affinity. For example, enterobactin (Ent) and bacillibactin (BB), which are produced by commensal bacteria including Escherichia coli , complex iron with extraordinary formation constants ( K f ) of 10 49 and 10 47 m −1 , respectively…”

“…[3] In humanp lasma, for example, the concentration of free Fe III is only about1 0 À24 m, essentially duet ot he complexation by transferrin. [4] However, to ensure an iron supply,m icrobes have evolveda ne laborate strategy: [5] They secrete so-calleds iderophores, smallo rganic molecules that chelate Fe III with extremely high affinity.F or example, enterobactin( Ent) and bacillibactin (BB), which are produced by commensal bacteria including Escherichia coli, complex iron with extraordinary formation constants (K f )o f 10 49 and 10 47 m À1 ,respectively. [6] Both Ent and BB belong to the catecholate family of siderophores and contain ac yclic trilactone backbone with three 2,3dihydroxybenzoyl side chains that can tightly coordinate acentral ferric ion ( Figure 1).…”

“…[9] Conversely,d ue to their critical role for pathogens, siderophores serve as targets for the innate immune system to suppressb acterial growth. [5] In this context, one of the most important proteins is siderocalin (Scn), also known as lipocalin 2( Lcn2) or neutrophil gelatinase-associated lipocalin (NGAL). [10] Scn is an abundant human plasma protein that tightly binds several siderophoresf rom the catecholatetype familyw ith sub-nanomolar K D values, in particular Ent·Fe III and BB·Fe III .Furthermore, it recognizess ome of the carboxymycobactins secretedb yMycobacterium tuberculosis,w hich com-Iron acquisition mediated by siderophores, high-affinity chelators for which bacteria have evolved specific synthesis and uptake mechanisms, plays ac rucial role in microbiology and in host-pathogen interactions.…”

Serum siderocalin levels in patients with tuberculosis and HIV infection

“…On the other hand, mammals have evolved mechanisms to limit the availability of iron to pathogens such as M. tuberculosis. These mechanisms include lowering of serum iron concentrations and increased secretion of the protein siderocalin (also known as lipocalin 2 and neutrophil gelatinase-associated lipocalin, NGAL) into extracellular fluids (Golonka et al, 2019;Wilson et al, 2016).…”