Lipocalin 2 and the iroA gene cluster in host iron defense and evasion Original paper

What was reviewed?

This review synthesizes mechanistic and translational evidence on lipocalin 2 and the iroA gene cluster at the host pathogen iron interface, focusing on how the innate immune protein lipocalin 2 sequesters catecholate siderophores such as enterobactin and how pathogens counter with the iroA-encoded salmochelin system to evade sequestration and sustain iron acquisition during infection.

Who was reviewed?

Evidence is drawn from structural biology, bacterial genetics, murine infection models, and clinical biomarker studies. Representative pathogens include Enterobacteriaceae such as uropathogenic Escherichia coli and Salmonella enterica that harbor iroA; Mycobacterium tuberculosis which produces long chain carboxymycobactins; and Bacillus anthracis which synthesizes petrobactin. Host tissues and cells surveyed include neutrophils, liver, spleen, kidney, and epithelial compartments where lipocalin 2 is either constitutively present or induced as part of the acute phase response.

Most important findings

The review establishes enterobactin as a high affinity tris-catecholate siderophore used by many Gram negative bacteria, while lipocalin 2 (also called NGAL or siderocalin) binds enterobactin family siderophores to block bacterial iron uptake. Bacterial evasion hinges on the iroA locus, which encodes glucosylation of enterobactin by IroB to form salmochelins and dedicated transport through IroN. Glucosylation at the 5 position on 2,3-dihydroxybenzoylserine moieties sterically prevents lipocalin 2 binding, preserving iron import under immune pressure. In vivo, iroA promotes urovirulence and systemic fitness of E. coli in mice, whereas simple enterobactin receptors lack independent virulence contributions.

Analogous evasion occurs with petrobactin in B. anthracis and with long chain carboxymycobactins in M. tuberculosis, supporting convergent pressure to bypass lipocalin 2. Beyond antimicrobial defense, lipocalin 2 rises early in renal tubular injury and sepsis, reflecting an acute phase profile that improves timing of detection relative to creatinine although clinical context is needed for interpretation. The diagram on page 7 (Figure 1) depicts this interface in detail, showing enterobactin biosynthesis and export, salmochelin modification and transport, TonB-dependent uptake through FepA or IroN, periplasmic shuttling via FepB and FepD/FepG/FepC, and host sensing through TLR and NLR pathways that induce lipocalin 2 secretion from neutrophils and macrophages to outcompete FepA for enterobactin, while salmochelin circumvents capture.

Key implications

For microbiome-aware pathogenesis, lipocalin 2 likely constrains Enterobacteriaceae lacking iroA within mucosal communities, while selection for iroA enables transition to invasive niches including the urinary tract and bloodstream. These patterns nominate major microbial associations for databases: iroA-positive E. coli and Salmonella as enriched in inflammatory or iron-restricted states, with lipocalin 2 acting as a host-side determinant of community structure. Therapeutically, the iroA cluster presents a narrow-spectrum virulence target that could re-sensitize pathogens to host iron withholding without broadly disturbing commensals, aligning with antimicrobial stewardship. Clinically, lipocalin 2 remains a promising early injury and infection biomarker, but its pleiotropic induction necessitates integration with additional diagnostics and clinical context.

Citation

Smith KD. Iron metabolism at the host pathogen interface: lipocalin 2 and the pathogen-associated iroA gene cluster. Int J Biochem Cell Biol. 2007;39(10):1776-1780. doi:10.1016/j.biocel.2007.07.003