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.

1.
Cunningham MW: Pathogenesis of group A streptococcal infections. Clin Microbiol Rev2000;13:470–511.
2.
Carapetis JR, Steer AC, Mulholl EK, Weber M: The global burden of group A streptococcal diseases. Lancet Infect Dis 2005;5:685–694.
3.
Telfer NR, Chalmers RJ, Whale K, Coleman G: The role of streptococcal infection in the initiation of guttate psoriasis. Arch Dermatol 1992;128:39–42.
4.
Rasmussen M, Björck L: Proteolysis and its regulation at the surface of Streptococcus pyogenes. Mol Microbiol 2002;43:537–544.
5.
Macpherson AJ, Uhr T: Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 2004;303:1662–1665.
6.
Kaetzel CS, Robinson JK, Chintalacharuvu KR, Vaerman JP, Lamm ME: The polymeric immunoglobulin receptor (secretory component) mediates transport of immune complexes across epithelial cells: a local defense function for IgA. Proc Natl Acad Sci USA 1991;88:8796–8800.
7.
Mistry D, Stockley RA: IgA1 protease. Int J Biochem Cell Biol 2006;38:1244–1248.
8.
Hauck CR, Meyer TF: The lysosomal/phagosomal membrane protein h-LAMP-1 is a target of the IgA1 protease of Neisseria gonorrhoeae. FEBS Letters 1997;405:86–90.
9.
Pleass RJ, Areschoug T, Lindahl G, Woof JM: Streptococcal IgA-binding proteins bind in the Cα2-Cα3 interdomain region and inhibit binding of IgA to human CD89. J Biol Chem 2001;276:8197–8204.
10.
Persson CG, Erjefält JS, Greiff L, Erjefält I, Korsgren M, Lindén M, Sundler F, Andersson M, Svensson C: Contribution of plasma-derived molecules to mucosal immune defence, disease and repair in the airways. Scand J Immunol 1998;47:302–313.
11.
Brezski RJ, Jordan RE: Cleavage of IgGs by proteases associated with invasive diseases: an evasion tactic against host immunity? MAbs 2010;2:212–220.
12.
Elliott SD: A proteolytic enzyme produced by group A streptococci with special reference to its effect on the type-specific M antigen. J Exp Med 1945;81:573–592.
13.
Collin M, Olsén A: EndoS, novel secreted enzyme from Streptococcus pyogenes with endoglycosidase activity on human IgG. EMBO J 2001;20:3046–3055.
14.
Eriksson A, Norgren M: Cleavage of antigen-bound immunoglobulin G by SpeB contributes to streptococcal persistence in opsonizing blood. Infect Immun 2003;71:211–217.
15.
von Pawel-Rammingen U, Björck L: IdeS and SpeB: immunoglobulin-degrading cysteine proteases of Streptococcus pyogenes. Curr Opin Microbiol 2003;6:50–55.
16.
von Pawel-Rammingen U, Johansson BP, Björck L: IdeS, a novel streptococcal cysteine proteinase with unique specificity for immunoglobulin G. EMBO J 2002;21:1607–1615.
17.
Lei B, Mackie S, Lukomski S, Musser JM: Identification and immunogenicity of group A streptococcus culture supernatant proteins. Infect Immun 2000;68:6807–6818.
18.
Lei B, DeLeo FR, Hoe NP, Graham MR, Mackie SM, Cole RL, Liu M, Hill HR, Low DE, Federle MJ, Scott JR, Musser JM: Evasion of human innate and acquired immunity by a bacterial homolog of CD11b that inhibits opsonophagocytosis. Nat Med 2001;7:1298–1305.
19.
Johansson Söderberg J, Engström P, von Pawel-Rammingen U: The intrinsic IgG endopeptidase activity of streptococcal Mac-2 proteins implies a unique role for the enzymatically impaired Mac-2 protein of M28 serotype strains. Infect Immun 2008;76:2183–2188.
20.
Lei B, DeLeo FR, Reid SD, Voyich JM, Magoun L, Liu M, Braughton KR, Ricklefs S, Hoe NP, Cole RL, Leong JM, Musser JM: Opsonophagocytosis-inhibiting Mac protein of group A streptococcus: identification and characteristics of two genetic complexes. Infect Immun 2002;12:6880–6890.
21.
Åkesson P, Moritz L, Truedsson M, Christensson B, von Pawel-Rammingen U: IdeS, a highly specific IgG-cleaving enzyme from Streptococcus pyogenes, is inhibited by specific IgG antibodies generated during infection. Infect Immun 2006;74:497–503.
22.
Åkesson P, Rasmussen M, Mascini E, von Pawel-Rammingen U, Janulczyk R, Collin M, Olsén A, Mattsson E, Olsson ML, Björck L, Christensson B: Low antibody titers to cell wall-attached proteins of Streptococcus pyogenes predispose for severe invasive disease. J Infect Dis 2004;189:797–804.
23.
Lannergård J, Guss B: IdeE, an IgG endopeptidase of Streptococcus equi ssp equi. FEMS Microbiol Lett 2006;262:230–235.
24.
Hulting G, Flock M, Fryckberg L, Lannergård J, Flock JI, Guss B: Two novel IgG endopeptidases of Streptococcus equi. FEMS Microbiol Lett 2009;298:44–50.
25.
Holden MT, Hauser H, Sanders M, Ngo TH, Cherevach I, Cronin A, Goodhead I, Mungall K, Quail MA, Price C, Rabbinowitsch E, Sharp S, Croucher NJ, Chieu TB, Mai NT, Diep TS, Chinh NT, Kehoe M, Leigh JA, Ward PN, Dowson CG, Whatmore AM, Chanter N, Iversen P, Gottschalk M, Slater JD, Smith HE, Spratt BG, Xu J, Ye C, Bentley S, Barrell BG, Schultsz C, Maskell DJ, Parkhill J: Rapid evolution of virulence and drug resistance in the emerging zoonotic pathogen Streptococcus suis. PLoS One 2009;4:e6072.
26.
Ishihara K, Wawrzonek K, Shaw LN, Inagaki S, Miyamoto M, Potempa J: Dentipain, a Streptococcus pyogenes IdeS protease homolog, is a novel virulence factor of Treponema denticola. Biol Chem 2010;391:1047–1055.
27.
Radaev S, Sun P: Recognition of immunoglobulins by Fc gamma receptors. Mol Immunol 2002;38:1073–1083.
28.
Duncan AR, Winter G: The binding site for C1q on IgG. Nature 1988;332:738–740.
29.
Vincents B, von Pawel-Rammingen U, Björck L, Abrahamson M: Biochemical characterization of IdeS, an IgG-specific endopeptidase from Streptococcus pyogenes. Biochemistry 2004;43:15540–15549.
30.
Ryan MH, Petrone D, Nemeth JF, Barnathan E, Björck L, Jordan RE: Proteolysis of purified IgGs by human and bacterial enzymes in vitro and the detection of specific proteolytic fragments of endogenous IgG in rheumatoid synovial fluid. Mol Immunol 2008;45:1837–1846.
31.
Brezski RJ, Vafa O, Petrone D, Tam SH, Powers G, Ryan MH, Luongo JL, Oberholtzer A, Knight DM, Jordan RE: Tumor-associated and microbial proteases compromise host IgG effector functions by a single cleavage proximal to the hinge. Proc Natl Acad Sci USA 2009;106:17864–17869.
32.
Vincents B, Vindebro R, Abrahamsson M, von Pawel-Rammingen U: Acceleration of cysteine protease activity by the human protease inhibitor cystatin C. Chem Biol 2008;15:960–968.
33.
Agniswamy J, Nagiec MJ, Liu M, Schuck P, Musser JM, Sun PD: Crystal structure of group A streptococcus Mac-1: insight into dimer-mediated specificity for recognition of human IgG. Structure 2006;14:225–235.
34.
Olsen JG, Dagil R, Niclasen LM, Sørensen OE, Kragelund BB: Structure of the mature streptococcal cysteine protease exotoxin mSpeB in its active dimeric form. J Mol Biol 2009;393:693–703.
35.
Wenig K, Chatwell L, von Pawel-Rammingen U, Björck L, Huber R, Sondermann P: Structure of the streptococcal endopeptidase IdeS, a novel cysteine proteinase with strict specificity for IgG. Proc Natl Acad Sci USA 2004;101:17371–17376.
36.
Lei B, Liu M, Meyers EG, Manning HM, Nagiec MJ, Musser JM: Histidine and aspartic acid residues important for immunoglobulin G endopeptidase activity of the group A streptococcus opsonophagocytosis-inhibiting Mac protein. Infect Immun 2003;5:2881–2884.
37.
Rawlings ND, Tolle DP, Barrett AJ: MEROPS: a peptidase database. Nucleic Acids Res 2004; 32:D160–D164.
38.
Turk B, Turk D, Salvesen GS: Regulating cysteine protease activity: essential role of protease inhibitors as guardians and regulators. Curr Pharm Des 2002;8:1623–1637.
39.
Scharfstein J: Parasite cysteine protease interactions with alpha2-macroglobulin or kininogens: differential pathways modulating inflammation and innate immunity in infection by pathogenic trypanosomatids.Immunobiology 2006;211:117–125.
40.
Björck L, Grubb A, Kjellén L: Cystatin C, a human protease inhibitor, blocks replication of Herpes simplex virus. J Virol 1990;64:941–943.
41.
Dossett JH, Kronvall G, Williams RC Jr, Quie PG: Antiphagocytic effects of staphylococcal protein A. J Immunol 1969;103:1405–1410.
42.
Pleass RJ, Areschoug T, Lindahl G, Woof JM: Streptococcal IgA-binding proteins bind in the Calpha 2-Calpha 3 interdomain region and inhibit binding of IgA to human CD89. J Biol Chem 2001;276:8197–8204.
43.
Berge A, Kihlberg BM, Sjöholm AG, Björck L: Streptococcal protein H forms soluble complement-activating complexes with IgG, but inhibits complement activation by IgG-coated targets. J Biol Chem 1997;272:20774–20781.
44.
Johansson Söderberg J, von Pawel-Rammingen U: The streptococcal protease IdeS modulates bacterial IgGFc binding and generates ½Fc fragments with the ability to prime polymorphonuclear leucocytes. Mol Immunol 2008;45:3347–3353.
45.
McPhail LC, Clayton CC, Snyderman R: The NADPH oxidase of human polymorphonuclear leukocytes: evidence for regulation by multiple signals. J Biol Chem 1984;259:5768–5775.
46.
Sheppard FR, Kelher MR, Moore EE, McLaughlin NJ, Banerjee A, Silliman CC: Structural organization of the neutrophil NADPH oxidase: phosphorylation and translocation during priming and activation. J Leukoc Biol 2005;78:1025–1042.
47.
Swain SD, Rohn TT, Quinn MT: Neutrophil priming in host defense: role of oxidants as priming agents. Antioxid Redox Signal 2002;4:69–83.
48.
Okamoto S, Tamura Y, Terao Y, Hamada S, Kawabata S: Systemic immunization with streptococcal immunoglobulin-binding protein Sib35 induces protective immunity against group A streptococcus challenge in mice. Vaccine 2005;23:4852–4859.
49.
Norrby-Teglund A, Pauksens K, Holm SE, Norgren M: Relation between low capacity of human serum to inhibit streptococcal mitogens and serious manifestation of disease. J Infect Dis 1994;170:585–591.
50.
Norrby-Teglund A, Kaul R, Low DE, McGeer A, Andersson J, Andersson U, Kotb M: Evidence for the presence of streptococcal-superantigen-neutralizing antibodies in normal polyspecific immunoglobulin G. Infect Immun 1996;64:5395–5398.
51.
Agniswamy J, Lei B, Musser JM, Sun PD: Insight of host immune evasion mediated by two variants of group A streptococcus Mac protein. J Biol Chem 2004;279:52789–52796.
52.
Kawabata S, Tamura Y, Murakami J, Terao Y, Nakagawa I, Hamada S: A novel, anchorless streptococcal surface protein that binds to human immunoglobulins. Biochem Biophys Res Commun 2002;296:1329–1333.
53.
Okamoto S, Terao Y, Tamura Y, Hamada S, Kawabata S: Streptococcal immunoglobulin-binding protein Sib35 exerts stimulatory and mitogenic effects towards mouse B lymphocytes. FEMS Microbiol Lett 2008;281:73–80.
54.
Hess JL, Porsch EA, Shertz CA, Boyle MD: Immunoglobulin cleavage by the streptococcal cysteine protease IdeS can be detected using protein G capture and mass spectrometry. J Microbiol Meth 2007;70:284–291.
55.
Berggren K, Johansson B, Fex T, Kihlberg J, Björck L, Luthman K: Synthesis and biological evaluation of reversible inhibitors of IdeS, a bacterial cysteine protease and virulence determinant. Bioorg Med Chem 2009;17:3463–3470.
56.
Berggren K, Vindebro R, Bergström C, Spoerry C, Persson H, Fex T, Kihlberg J, von Pawel-Rammingen U, Luthman K: 3-Aminopiperidine-based peptide analogues as selective noncovalent inhibitors of the bacterial cysteine protease IdeS. J Med Chem 2011 (in press).
57.
Johansson BP, Shannon O, Björck L: IdeS: a bacterial proteolytic enzyme with therapeutic potential. PLoS One 2008;3:e1692.
58.
Nandakumar KS, Johansson BP, Björck L, Holmdahl R: Blocking of experimental arthritis by cleavage of IgG antibodies in vivo. Arthritis Rheum 2007;56:3253–3260.
59.
Yang R, Otten MA, Hellmark T, Collin M, Björck L, Zhao MH, Daha MR, Segelmark M: Successful treatment of experimental glomerulonephritis with IdeS and EndoS, IgG-degrading streptococcal enzymes. Nephrol Dial Transplant 2010;8:2479–2486.
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