The Molecular Basis of Human IgG-Mediated Enhancement of C4b-Binding Protein Recruitment to Group A Streptococcus
Blom, Anna M.
UMass Chan AffiliationsDepartment of Medicine, Division of Infectious Diseases and Immunology
Document TypeJournal Article
KeywordsStreptococcus pyogenes (S. pyogenes)
immunoglobulin G (IgG)
the complement system
Amino Acids, Peptides, and Proteins
Bacterial Infections and Mycoses
Biochemistry, Biophysics, and Structural Biology
Immunology of Infectious Disease
MetadataShow full item record
AbstractStreptococcus pyogenes infects over 700 million people worldwide annually. Immune evasion strategies employed by the bacteria include binding of the complement inhibitors, C4b-binding protein (C4BP) and Factor H in a human-specific manner. We recently showed that human IgG increased C4BP binding to the bacterial surface, which promoted streptococcal immune evasion and increased mortality in mice. We sought to identify how IgG promotes C4BP binding to Protein H, a member of the M protein family. Dimerization of Protein H is pivotal for enhanced binding to human C4BP. First, we illustrated that Protein H, IgG, and C4BP formed a tripartite complex. Second, surface plasmon resonance revealed that Protein H binds IgG solely through Fc, but not Fab domains, and with high affinity (IgG-Protein H: KD = 0.4 nM; IgG-Fc-Protein H: KD < /= 1.6 nM). Each IgG binds two Protein H molecules, while up to six molecules of Protein H bind one C4BP molecule. Third, interrupting Protein H dimerization either by raising temperature to 41 degrees C or with a synthetic peptide prevented IgG-Protein H interactions. IgG-Fc fragments or monoclonal human IgG permitted maximal C4BP binding when used at concentrations from 0.1 to 10 mg/ml. In contrast, pooled human IgG enhanced C4BP binding at concentrations up to 1 mg/ml; decreased C4BP binding at 10 mg/ml occurred probably because of Fab-streptococcal interactions at these high IgG concentrations. Taken together, our data show how S. pyogenes exploits human IgG to evade complement and enhance its virulence. Elucidation of this mechanism could aid design of new therapeutics against S. pyogenes.
Front Immunol. 2019 Jun 4;10:1230. doi: 10.3389/fimmu.2019.01230. eCollection 2019. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/41087
RightsCopyright © 2019 Ermert, Laabei, Weckel, Mörgelin, Lundqvist, Björck, Ram, Linse and Blom. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Except where otherwise noted, this item's license is described as Copyright © 2019 Ermert, Laabei, Weckel, Mörgelin, Lundqvist, Björck, Ram, Linse and Blom. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
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