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Thromb Haemost 2015; 113(01): 125-142
DOI: 10.1160/TH14-06-0561
Blood Cells, Inflammation and Infection
Schattauer GmbH

Binding of vitronectin and Factor H to Hic contributes to immune evasion of Streptococcus pneumoniae serotype 3

Sylvia Kohler
1   Department Genetics of Microorganisms, Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany
,
Teresia Hallström
2   Department of Infection Biology, Hans Knoell Institute, Leibniz Institute for Natural Product Research and Infection Biology, Jena
,
Birendra Singh
3   Medical Microbiology, Department of Laboratory Medicine Malmö, Lund University, Malmö, Sweden
,
Kristian Riesbeck
3   Medical Microbiology, Department of Laboratory Medicine Malmö, Lund University, Malmö, Sweden
,
Giuseppina Spartà
4   University Children´s Hospital, Zurich, Switzerland
,
Peter F. Zipfel
2   Department of Infection Biology, Hans Knoell Institute, Leibniz Institute for Natural Product Research and Infection Biology, Jena
5   Friedrich Schiller University, Jena, Germany
,
Sven Hammerschmidt
1   Department Genetics of Microorganisms, Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany
› Author Affiliations Financial support: This work was supported by Grants from the Deutsche Forschungsgemeinschaft DFG HA 3125/4-2 and the DFG-GRK840 (to S. H.) as well as the Anna and Edwin Berger foundation and the Swedish Medical Research Council (grant number 521-2010-4221) (to K. R.).
Further Information

Publication History

Received: 28 June 2014

Accepted after minor revision: 24 July 2014

Publication Date:
27 November 2017 (online)

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Summary

Streptococcus pneumoniae serotype 3 strains are highly resistant to opsonophagocytosis due to recruitment of the complement inhibitor Factor H via Hic, a member of the pneumococcal surface protein C (PspC) family. In this study, we demonstrated that Hic also interacts with vitronectin, a fluid-phase regulator involved in haemostasis, angiogenesis, and the terminal complement cascade as well as a component of the extracellular matrix. Blocking of Hic by specific antiserum or genetic deletion significantly reduced pneumococcal binding to soluble and immobilised vitronectin and to Factor H, respectively. In parallel, ectopic expression of Hic on the surface of Lactococcus lactis conferred binding to soluble and immobilised vitronectin as well as Factor H. Molecular analyses with truncated Hic fragments narrowed down the vitronectin-binding site to the central core of Hic (aa 151–201). This vitronectin-binding region is separate from that of Factor H, which binds to the N-terminus of Hic (aa 38–92). Binding of pneumococcal Hic was localised to the C-terminal heparin-binding domain (HBD3) of vitronectin. However, an N-terminal region to HBD3 was further involved in Hic-binding to immobilised vitronectin. Finally, vitronectin bound to Hic was functionally active and inhibited formation of the terminal complement complex. In conclusion, Hic interacts with vitronectin and simultaneously with Factor H, and both human proteins may contribute to colonisation and invasive disease caused by serotype 3 pneumococci.

Keywords

Complement - Hic - pathogenesis - PspC11 - serotype 3 - Streptococcus pneumoniae - vitronectin
 

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