The Staphylococcus aureus Protein IsdH Inhibits Host Hemoglobin Scavenging to Promote Heme Acquisition by the Pathogen

Abstract

Edited by F. Peter GuengerichHemolysis is a complication in septic infections with Staphylococcus aureus, which utilizes the released Hb as an iron source. S. aureus can acquire heme in vitro from hemoglobin (Hb) by a heme-sequestering mechanism that involves proteins from the S. aureus iron-regulated surface determinant (Isd) system. However, the host has its own mechanism to recapture the free Hb via haptoglobin (Hp) binding and uptake of Hb-Hp by the CD163 receptor in macrophages. It has so far remained unclear how the Isd system competes with this host iron recycling system in situ to obtain the important nutrient.

Energetics underlying hemin extraction from human hemoglobin by Staphylococcus aureus

“…Thus, despite burying similar solvent-exposed surface areas, the N2⅐Hb interface is the primary determinant for overall binding affinity, whereas the LN3⅐Hb interface forms with very weak affinity because of the large enthalpic penalty that must be paid to distort Hb's F-helix. Recently, binding of IsdH to the Hb⅐Hp complex was studied by surface plasmon resonance, and it was reported that native IsdH N2N3 binds Hb-Hp with a K D ϳ 120 nM (57), which is an order of magnitude higher in affinity than our ITC measured affinity of the Hb⅐IsdH N2N3 complex. This difference may result from the distinct methods that were employed.…”

“…As these receptors do not contact Hp directly, it is possible that subtle Hp-induced changes in the structure of Hb may increase its binding affinity for IsdH and IsdB. However, remarkably Hp binding prevents hemin transfer from Hb to IsdB in the ternary complex (57). Thus, the Hp-induced conformational changes prevent hemin dissociation with and without bound receptor (59).…”

Corynebacterium diphtheriae Iron-Regulated Surface Protein HbpA Is Involved in the Utilization of the Hemoglobin-Haptoglobin Complex as an Iron Source

“…A study that examined the role of S. aureus IsdH, a protein known to bind Hb-Hp, showed that an isdH mutant exhibited growth equivalent to that of the wild-type strain when Hb-Hp was the sole iron source (57), suggesting that either IsdH is not involved in the use of Hb-Hp or that other proteins may also be involved in the acquisition of hemin iron from Hb-Hp. While IsdB and Shr are known to bind Hb-Hp (28,38), their involvement in the use of the hemoprotein as an iron source has not been reported; both proteins are active in the use of Hb as an iron source (23,36). It has not been determined whether the IsdX1, IsdX2, and Hal proteins in B. anthracis can bind Hb-Hp or utilize this hemoprotein as an iron source.…”

“…It has not been determined whether the IsdX1, IsdX2, and Hal proteins in B. anthracis can bind Hb-Hp or utilize this hemoprotein as an iron source. A recent study reported that the S. aureus IsdH and IsdB proteins can bind Hb-Hp in vitro, but only IsdH was shown to remove hemin from Hb-Hp and to inhibit binding of Hb-Hp to its cellular receptor, CD163 (28). IsdH was also shown to inhibit the uptake of Hb-Hp by CD163-expressing cells, a function that IsdB was unable to perform.…”

“…The hemin transport system in Staphylococcus aureus has been extensively studied and shown to utilize seven surface proteins, designated iron-regulated surface determinants (Isd), to transport hemin (25). The surface-exposed IsdB and IsdH proteins are initially involved in binding hemoglobin (Hb) and the hemoglobin-haptoglobin complex (Hb-Hp) at the surface of the bacteria using unique binding regions known as NEAT (near iron transporter) domains (12,(25)(26)(27)(28). These proteins extract the hemin from hemoproteins, where the hemin is subsequently moved through the cell wall by a relay mechanism that involves the cell wall-anchored proteins IsdA and IsdC (29,30).…”