The Staphylococcus aureus Protein IsdH Inhibits Host Hemoglobin Scavenging to Promote Heme Acquisition by the Pathogen.
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, IsdHN1, IsdHN2, and IsdHN3, revealed that Hb binding of IsdHN1and IsdHN2accounted for the high affinity for Hb-Hp complexes. The third near iron transporter domain, IsdHN3, 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.
From the Department of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark.
Kirstine Lindhardt
KL
Sæderup
the Department of Biomedicine and.
Kristian
K
Stødkilde
From the Department of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark.
Jonas Heilskov
JH
Graversen
the School of Medicine, University of Tasmania, Hobart, Tasmania 7005, Australia, and.
Claire F
CF
Dickson
the Department of Biomedicine and.
Anders
A
Etzerodt
From the Department of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark.
Søren Werner Karlskov
SW
Hansen
Zoophysiology Section, Department of Bioscience, Aarhus University, DK-8000 Aarhus, Denmark.
Angela
A
Fago
the School of Medicine, University of Tasmania, Hobart, Tasmania 7005, Australia, and.
David
D
Gell
the Department of Biomedicine and.
Christian Brix Folsted
CB
Andersen
From the Department of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark, smoestrup@health.sdu.dk.|the Department of Biomedicine and.|the Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, 5000 Odense, Denmark.
Søren Kragh
SK
Moestrup
D000818:Animals; D000942:Antigens, Bacterial; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000378:metabolism; D016466:CHO Cells; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D006242:Haptoglobins / Q000378:metabolism*; D006418:Heme / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D000072417:Protein Domains; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D013211:Staphylococcus aureus / Q000235:genetics / Q000378:metabolism*; D000098902:CD163 Antigen
D000942:Antigens, Bacterial; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D027682:Cation Transport Proteins; D006242:Haptoglobins; C510010:IsdB protein, Staphylococcus aureus; C512792:IsdH protein, Staphylococcus aureus; D011956:Receptors, Cell Surface; D006418:Heme
CD163; Iron-regulated Surface Determinant; IsdH; Staphylococcus aureus (S. aureus); cell surface receptor; haptoglobin; heme acquisition; hemoglobin; iron; macrophage
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