TY - JOUR
T1 - The Staphylococcus aureus Protein IsdH Inhibits Host Hemoglobin Scavenging to Promote Heme Acquisition by the Pathogen
AU - Saederup, Kirstine Lindhardt
AU - Stødkilde-Jørgensen, Kristian
AU - Graversen, Jonas Heilskov
AU - Dickson, Claire F.
AU - Etzerodt, Anders
AU - Hansen, Soren Werner Karlskov
AU - Fago, Angela
AU - Gell, David
AU - Andersen, Christian Brix Folsted
AU - Moestrup, Soren Kragh
PY - 2016/11/11
Y1 - 2016/11/11
N2 - 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.
AB - 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.
KW - cell surface receptor
KW - hemoglobin
KW - iron
KW - macrophage
KW - Staphylococcus aureus (S
KW - aureus)
KW - CD163
KW - Iron-regulated Surface Determinant
KW - IsdH
KW - haptoglobin
KW - heme acquisition
KW - CYSTEINE-RICH DOMAIN
KW - RECEPTOR CD163
KW - TRANSPORTER DOMAINS
KW - SURFACE PROTEIN
KW - MOLECULAR-BASIS
KW - HAPTOGLOBIN
KW - IRON
KW - BINDING
KW - COMPLEX
KW - SUSCEPTIBILITY
UR - http://www.scopus.com/inward/record.url?scp=84995578540&partnerID=8YFLogxK
U2 - 10.1074/jbc.M116.755934
DO - 10.1074/jbc.M116.755934
M3 - Journal article
C2 - 27681593
SN - 0021-9258
VL - 291
SP - 23989
EP - 23998
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 46
ER -