Iron-Regulated Surface Determinant (Isd) Proteins of Staphylococcus lugdunensis

Abstract

bStaphylococcus lugdunensis is the only coagulase-negative Staphylococcus species with a locus encoding iron-regulated surface determinant (Isd) proteins. In Staphylococcus aureus, the Isd proteins capture heme from hemoglobin and transfer it across the wall to a membrane-bound transporter, which delivers it into the cytoplasm, where heme oxygenases release iron. The Isd proteins of S. lugdunensis are expressed under iron-restricted conditions. We propose that S. lugdunensis IsdB and IsdC proteins perform the same functions as those of S. aureus. S. lugdunensis IsdB is the only hemoglobin receptor within the isd locus. It specifically binds human hemoglobin with a dissociation constant (K d ) of 23 nM and transfers heme on IsdC. IsdB expression promotes bacterial growth in an iron-limited medium containing human hemoglobin but not mouse hemoglobin. This correlates with weak binding of IsdB to mouse hemoglobin in vitro. Unlike IsdB and IsdC, the proteins IsdJ and IsdK are not sorted to the cell wall in S. lugdunensis. In contrast, IsdJ expressed in S. aureus and Lactococcus lactis is anchored to peptidoglycan, suggesting that S. lugdunensis sortases may differ in signal recognition or could be defective. IsdJ and IsdK are present in the culture supernatant, suggesting that they could acquire heme from the external milieu. The IsdA protein of S. aureus protects bacteria from bactericidal lipids due to its hydrophilic C-terminal domain. IsdJ has a similar region and protected S. aureus and L. lactis as efficiently as IsdA but, possibly due to its location, was less effective in its natural host.

Multi-Virulence-Locus Sequence Typing of Staphylococcus lugdunensis Generates Results Consistent with a Clonal Population Structure and Is Reliable for Epidemiological Typing

“…As systems to genetically manipulate S. lugdunensis succeeded only very recently (21,22), a few virulent factors are known to date. We selected (27,30) and IsdJ, a protein of an iron acquisition system, which of the CoNS, is only used by S. lugdunensis (30,32). Besides theses virulence-associated loci, we analyzed the polymorphisms of the repeated sequences (atlL R2 and atlL R3 ) of the putative CWA domains of the AM and GL autolysins, respectively, generated by the proteolytic cleavage of the bifunctional murein hydrolase, AtlL (40).…”

“…Besides, S. lugdunensis is unique among the CoNS in that it contains a gene encoding an ironregulated surface determinant (Isd) system (30), which shares significant structural and functional homology with the Isd receptors of S. aureus. Under iron-restricted conditions, the Isd proteins cooperate to capture heme and transfer it across the wall into the cytoplasm, where it is degraded to iron for use in cellular processes (31,32). Interestingly, the genome sequencing of two strains of S. lugdunensis, N920143 (30) and HKU09-01 (33), revealed genes encoding putative virulence factors, such as adhesins, toxins, and hemolysins.…”

IsdC from Staphylococcus lugdunensis Induces Biofilm Formation under Low-Iron Growth Conditions

“…Both systems are expressed under iron-restricted conditions (28,29). Four of the S. lugdunensis Isd proteins are anchored to the cell wall peptidoglycan by sortases.…”

IruO Is a Reductase for Heme Degradation by IsdI and IsdG Proteins in Staphylococcus aureus

“…Staphylococcus lugdunensis contains an Isd heme import system similar to that of S. aureus (67) and has an experimentally characterized IsdG protein (68) that shares Ͼ60% amino acid sequence identity with S. aureus IsdG and IsdI. The genome of S. lugdunensis (69) contains a PNDO (SLUG_06580) that shares 68% amino acid sequence identity with S. aureus IruO, is similarly organized in a two-gene operon with an acetyltransferase, and is the protein most similar to S. aureus IruO in our phylogenetic analysis (Fig.…”