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

J Innate Immun. 2019;11(3):249-262. doi: 10.1159/000494627. Epub 2019 Jan 3.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Cyclic GMP / analogs & derivatives
  • Cyclic GMP / physiology
  • Ferrous Compounds / pharmacology
  • Host Microbial Interactions*
  • Humans
  • Immunity, Innate*
  • Inflammation / etiology
  • Iron / metabolism*
  • Lipocalin-2 / physiology
  • Neutrophils / physiology
  • Peptides / pharmacology
  • Reactive Oxygen Species / metabolism
  • Siderophores / chemistry
  • Siderophores / physiology*

Substances

  • Ferrous Compounds
  • Lipocalin-2
  • Peptides
  • Reactive Oxygen Species
  • Siderophores
  • sideromycins
  • bis(3',5')-cyclic diguanylic acid
  • Iron
  • Cyclic GMP