The streptococcal protease IdeS modulates bacterial IgGFc binding and generates 1/2Fc fragments with the ability to prime polymorphonuclear leucocytes

Mol Immunol. 2008 Jul;45(12):3347-53. doi: 10.1016/j.molimm.2008.04.013. Epub 2008 Jun 3.

Abstract

The important human bacterial pathogen Streptococcus pyogenes has evolved a variety of mechanisms to evade the actions of the human immune system. M protein and M-like proteins are major virulence factors that bind with high affinity to the Fc-part of IgG. However, the contribution of non-immune binding of IgG to bacterial virulence is not fully established. Importantly, the capacity of S. pyogenes to bind IgG is limited and due to the presence of large amounts of IgG present in vivo, the majority of IgGFc binding sites at the streptococcal surface are likely to be occupied by non-specific IgG. S. pyogenes also secretes a highly effective IgG-endopeptidase, IdeS that inhibits phagocytic killing by cleavage of specific IgG creating F(ab')2 and 1/2Fc fragments. In the present work, IgG and 1/2Fc binding to the streptococcal surface was studied and correlated to IdeS activity. Binding of IgG to the streptococcal surface is shown to be equilibrium and thus not designed to mediate a lasting protection against specific antibodies. However, non-immune binding of IgG to the bacterial surface is followed by the proteolytic cleavage of the antibody by the IgG-endopeptidase IdeS. IdeS generated 1/2Fc fragments do not compete efficiently with intact IgG in binding to the bacterial surface and rapid dissociation of 1/2Fc allows binding of new IgG. Thus, a correlated binding and proteolytic cleavage of IgG also increases the probability that the bacteria can resist specific IgG, despite the presence of a large excess of non-specific IgG in the circulation. As a consequence of IdeS activity, circulating 1/2Fc fragments are generated. These 1/2Fc fragments were shown to be biological active by acting as priming agents for polymorphonuclear leucocytes, suggesting a new mechanism of immune evasion employed by S. pyogenes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / metabolism*
  • Bacteriolysis
  • Humans
  • Immunoglobulin Fc Fragments / immunology*
  • Immunoglobulin Fc Fragments / isolation & purification
  • Immunoglobulin Fc Fragments / metabolism
  • Immunoglobulin G / blood
  • Microbial Viability
  • Neutrophils / cytology*
  • Neutrophils / immunology*
  • Protein Binding
  • Reactive Oxygen Species / metabolism
  • Streptococcus pyogenes / immunology

Substances

  • Bacterial Proteins
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • Mac-1-like protein, Streptococcus
  • Reactive Oxygen Species