Department of Biology

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Søren Kragh Moestrup

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

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DOI

  • Kirstine Lindhardt Saederup, Univ Southern Denmark, University of Southern Denmark, Dept Mol Med
  • ,
  • Kristian Stødkilde-Jørgensen
  • ,
  • Jonas Heilskov Graversen, Univ Southern Denmark, University of Southern Denmark, Dept Mol Med
  • ,
  • Claire F. Dickson, Univ Tasmania, University of Tasmania, Sch Med
  • ,
  • Anders Etzerodt
  • Soren Werner Karlskov Hansen, Univ Southern Denmark, University of Southern Denmark, Dept Mol Med
  • ,
  • Angela Fago
  • David Gell, Univ Tasmania, University of Tasmania, Sch Med
  • ,
  • Christian Brix Folsted Andersen
  • Soren Kragh Moestrup

Hemolysis 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. By binding and uptake studies, we now show that the IsdH protein, which serves as an Hb receptor in the Isd system, directly interferes with the CD163-mediated clearance by binding the Hb-Hp complex and inhibiting CD163 recognition. Analysis of truncated IsdH variants including one or more of three near iron transporter domains, IsdH(N1), IsdH(N2), and IsdH(N3), revealed that Hb binding of IsdH(N1) and IsdH(N2) accounted for the high affinity for Hb-Hp complexes. The third near iron transporter domain, IsdH(N3), exhibited redox-dependent heme extraction, when Hb in the Hb-Hp complex was in the oxidized met form but not in the reduced oxy form. IsdB, the other S. aureus Hb receptor, failed to extract heme from Hb-Hp, and it was a poor competitor for Hb-Hp binding to CD163. This indicates that Hb recognition by IsdH, but not by IsdB, sterically inhibits the receptor recognition of Hb-Hp. This function of IsdH may have an overall stimulatory effect on S. aureus heme acquisition and growth.

Original languageEnglish
JournalJournal of Biological Chemistry
Volume291
Issue46
Pages (from-to)23989-23998
Number of pages10
ISSN0021-9258
DOIs
Publication statusPublished - 11 Nov 2016

    Research areas

  • cell surface receptor, hemoglobin, iron, macrophage, Staphylococcus aureus (S, aureus), CD163, Iron-regulated Surface Determinant, IsdH, haptoglobin, heme acquisition, CYSTEINE-RICH DOMAIN, RECEPTOR CD163, TRANSPORTER DOMAINS, SURFACE PROTEIN, MOLECULAR-BASIS, HAPTOGLOBIN, IRON, BINDING, COMPLEX, SUSCEPTIBILITY

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