Human Tear Lipocalin Exhibits Antimicrobial Activity by Scavenging Microbial Siderophores

Abstract

Human tear lipocalin (TL; also known as Lcn1) is a secretory protein present in large amounts in fluids that cover epithelial surfaces such as tears and respiratory secretions. It is supposed to act as a physiological scavenger of hydrophobic, potentially harmful molecules, but there is evidence that it also inhibits bacterial growth. In the present study, we reconsidered the possibility that TL might interfere with microbial growth by scavenging of siderophores, as described for human neutrophil gelatinase-associated lipocalin (NGAL). Indeed, our experiments revealed that TL binds to microbial siderophores with high affinities. In contrast to NGAL, which was shown to have some specificity for bacterial catecholate-type siderophores, TL binds to a broad array of siderophores, including bacterial catecholate-type enterobactin and hydroxamate-type desferrioxamine B, and all major classes of fungal siderophores. By adding exogenous TL, bacterial and fungal growth could be inhibited under iron-limiting conditions. Thus, TL might be a novel member of the innate immune system especially involved in mucosal defense against fungal infections.

Iron acquisition in the cystic fibrosis lung and potential for novel therapeutic strategies

“…More than half of the total bodily iron is bound to haemoglobin in erythrocytes, approximately a quarter of bodily iron is stored within cells bound to ferritin and transferrin chaperones iron in plasma (Ganz & Nemeth, 2015). These proteins, together with other iron-sequestering proteins including lipocalins that sequester iron from bacterial siderophores (Goetz et al, 2002;Fluckinger et al, 2004), play a significant role in iron-targeted nutritional immunity. The battle between host iron sequestration and Staphylococcus aureus iron acquisition typifies these complex relationships, and is detailed in a review by Haley & Skaar (2012).…”

A genetic locus required for iron acquisition in Mycobacterium tuberculosis

“…Because iron is an essential cofactor for several enzymatic processes, restricting the availability of iron is an important strategy for defense against bacterial infections (1,2). Siderophores are typically low molecular weight peptidic metabolites that are specifically induced in response to low iron concentrations (3,4).…”

Evidence for internal and external binding sites on human tear lipocalin

“…It is the principal lipid binding protein in tears with ligands that include fatty acids, alkyl alcohols, glycolipids, phospholipids and cholesterol [7]. TL binds a host of other biologically important compounds including sapid molecules [8], retinol [9], potentially harmful lipid oxidation products [10], antioxidants [11], and fungal siderphores [12]. Several putative functions have been assigned to TL such as scavenging lipid from the corneal surface to prevent the formation of lipid induced dry spots [13], solubilization of lipid in tears (2), antimicrobial activity [14], cysteine proteinase inhibition [15], endonuclease activity [16] and scavenging of toxic molecules [10].…”