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

Kirstine Lindhardt Sæderup (Madsen), Kristian Stødkilde, Jonas Heilskov Graversen, Claire F Dickson, Anders Etzerodt, Søren Werner Karlskov Hansen, Angela Fago, David Gell, Christian Brix Folsted Andersen, Søren Kragh Moestrup

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Resumé

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.

OriginalsprogEngelsk
TidsskriftJournal of Biological Chemistry
Vol/bind291
Udgave nummer46
Sider (fra-til)23989-23998
ISSN0021-9258
DOI
StatusUdgivet - 2016

Fingeraftryk

Scavenging
Pathogens
Heme
Hemoglobins
Iron
Haptoglobins
Staphylococcus aureus IsdH protein
Protein S
Recycling
Hemolysis
Macrophages
Nutrients
Food

Citer dette

Lindhardt Sæderup (Madsen), Kirstine ; Stødkilde, Kristian ; Graversen, Jonas Heilskov ; Dickson, Claire F ; Etzerodt, Anders ; Hansen, Søren Werner Karlskov ; Fago, Angela ; Gell, David ; Andersen, Christian Brix Folsted ; Moestrup, Søren Kragh. / The Staphylococcus aureus Protein IsdH Inhibits Host Hemoglobin Scavenging to Promote Heme Acquisition by the Pathogen. I: Journal of Biological Chemistry. 2016 ; Bind 291, Nr. 46. s. 23989-23998.
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title = "The Staphylococcus aureus Protein IsdH Inhibits Host Hemoglobin Scavenging to Promote Heme Acquisition by the Pathogen",
abstract = "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.",
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The Staphylococcus aureus Protein IsdH Inhibits Host Hemoglobin Scavenging to Promote Heme Acquisition by the Pathogen. / Lindhardt Sæderup (Madsen), Kirstine; Stødkilde, Kristian; Graversen, Jonas Heilskov; Dickson, Claire F; Etzerodt, Anders; Hansen, Søren Werner Karlskov; Fago, Angela; Gell, David; Andersen, Christian Brix Folsted; Moestrup, Søren Kragh.

I: Journal of Biological Chemistry, Bind 291, Nr. 46, 2016, s. 23989-23998.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - The Staphylococcus aureus Protein IsdH Inhibits Host Hemoglobin Scavenging to Promote Heme Acquisition by the Pathogen

AU - Lindhardt Sæderup (Madsen), Kirstine

AU - Stødkilde, Kristian

AU - Graversen, Jonas Heilskov

AU - Dickson, Claire F

AU - Etzerodt, Anders

AU - Hansen, Søren Werner Karlskov

AU - Fago, Angela

AU - Gell, David

AU - Andersen, Christian Brix Folsted

AU - Moestrup, Søren Kragh

N1 - © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

PY - 2016

Y1 - 2016

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.

U2 - 10.1074/jbc.M116.755934

DO - 10.1074/jbc.M116.755934

M3 - Journal article

VL - 291

SP - 23989

EP - 23998

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 46

ER -