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The Staphylococcus aureus protein IsdH inhibits host hemoglobin scavenging to promote heme acquisition by the pathogen


Saederup, KL and Stodkilde, K and Graversen, JH and Dickson, CF and Etzerodt, A and Hansen, SWK and Fago, A and Gell, A and Andersen, CBF and Moestrup, SK, The Staphylococcus aureus protein IsdH inhibits host hemoglobin scavenging to promote heme acquisition by the pathogen, Journal of Biological Chemistry, 291, (46) pp. 23989-23997. ISSN 0021-9258 (2016) [Refereed Article]


Copyright Statement

Copyright 2016 The American Society for Biochemistry and Molecular Biology, Inc.

DOI: doi:10.1074/jbc.M116.755934


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 IsdHN1 and IsdHN2 accounted 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.

Item Details

Item Type:Refereed Article
Keywords:CD163, iron-regulated surface determinant, IsdH, Staphylococcus aureus (S. aureus), cell surface receptor, haptoglobin, heme acquisition, hemoglobin, iron, macrophage
Research Division:Biomedical and Clinical Sciences
Research Group:Medical microbiology
Research Field:Medical bacteriology
Objective Division:Expanding Knowledge
Objective Group:Expanding knowledge
Objective Field:Expanding knowledge in the biological sciences
UTAS Author:Dickson, CF (Miss Claire Dickson)
UTAS Author:Gell, A (Dr David Gell)
ID Code:118345
Year Published:2016
Web of Science® Times Cited:18
Deposited By:Medicine
Deposited On:2017-07-11
Last Modified:2022-08-30
Downloads:122 View Download Statistics

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