Streptococcal IdeS and its impact on immune response and inflammation

Abstract

Survival of the important bacterial pathogen Streptococcus pyogenes relies on its ability to circumvent the antimicrobial actions of innate and specific immune responses and to modulate the inflammatory responses induced during the course of an infection. Inflammatory processes play key roles during streptococcal pathogenesis and streptococcal infections are accompanied by an intense inflammatory state. As an exclusively human pathogen, S. pyogenes has adapted to the various countermeasures employed by its host to fight bacterial infections, in particular to interfere with the effector functions of immunoglobulin G (IgG). For this purpose, S. pyogenes has evolved an IgG-specific endopeptidase, IdeS, which is highly specific for the lower hinge region of IgG. This review summarizes the current knowledge about this intriguing enzyme as well as its role in inflammation and in the attenuation of human immune responses towards streptococcal infection.

Fig. 1

Overview of features and functions of streptococcal IdeS. A Powering IdeS activity. Interaction of IdeS with the abundant cysteine protease inhibitor cystatin C accelerates IgG endopeptidase activity. B IdeS biological activity. a S. pyogenes, recognized by specific IgG and/or binding IgG to M protein at the streptococcal surface, secrete active IdeS. b In the circulation, IdeS cleaves IgG in the hinge region, generating single-cleaved inactive IgG, F(ab′)₂ fragments and two identical ½Fc fragments. c Specific IgG at the streptococcal surface is efficiently cleaved by IdeS, leaving antigen bound F(ab′)₂ fragments that protect streptococcal surface antigens and releasing ½Fc fragments. Fc-bound IgG is also cleaved, releasing F(ab′)₂ fragments and, due to their low affinity for M-protein, ½Fc fragments into the circulation. Free binding sites at M protein can bind new IgG. d Circulating Fc fragments prime polymorphonuclear leukocytes (PMN) to an increased and fast production of ROS by binding to a yet-unknown receptor. Upon activation by immunocomplexes, these PMNs discharge and degranulate at a distance from the infection site without harming the bacteria. e Suppression of ROS production by IdeS to prevent PMNs to discharge close to the bacteria; IdeS suppresses ROS production, independently from its IgG endopeptidase activity. The precise mechanism so far remains elusive, but might be mediated by interaction with FcγR.