化膿性鏈球菌，又稱A群鏈球菌 (Streptococcus pyogenes；Group A Streptococcus；GAS) 為一重要之人類致病菌，能夠引起多種嚴重程度不等的疾病，輕微如咽喉炎；重則產生嚴重之侵襲性及致命之併發症，包括壞死性肌膜炎 (necrotizing fasciitis)、鏈球菌毒性休克症候群 (streptococcal toxic shock syndrome) 等。emm基因轉譯之蛋白質﹣M蛋白 (M protein)，是一重要之致病因子，在全世界廣泛的用來作為流行病學上的標記以區別化膿性鏈球菌血清型。emm分型與脈衝式電泳是二大重要的監視工具作為監測化膿性鏈球菌感染的依據。為了研究南台灣過去十年化膿性鏈球菌感染之流行病學動態變化，242個臨床檢體包含了76個從侵襲性病人、89個從猩紅熱病人以及77個從咽喉炎病人身上分離出來的檢體進行分子分型分析，以emm基因定序方法以及脈衝式電泳方式做分型分析。我們觀察到出現頻率最高的emm分型分別為12型 (43.4%)、4型 (18.2%) 和1型 (16.9%)。emm12型在2005和2007年的出現頻率達到高峰。有趣的是emm11型在我們的研究中發現都是由侵襲性病人身上分離而來。化膿性鏈球菌製造非常多樣的毒性因子以造成人類多樣性疾病，例如化膿性鏈球菌免疫球蛋白G分解酶 (Immunoglobulin G-degrading enzyme of Streptococcus pyogenes；簡稱IdeS) 和化膿性鏈球菌熱原性外毒素B (SpeB) 等。IdeS會經由切割免疫球蛋白G鉸鍊區 (hinge region) 來幫助A群鏈球菌逃避人類先天性免疫反應 (innate immunity) 並抑制抗體調節的吞噬作用。為了更瞭解IdeS在化膿性鏈球菌感染致病機制中的角色，155個檢體進行抗體效價以及ideS基因序列的分析。結果可觀察到侵襲性病人對於IdeS的抗體效價高於非侵襲性病人，雖然此一結果不具統計上之意義 (P = 0.07)；然而再進一步分析侵襲性病人血清，發現針對IdeS的抗體效價在嚴重的侵襲性病人中是低於較不嚴重的侵襲性病人 (P = 0.03)，顯示IdeS可能在嚴重的侵襲性病程發展中扮演一重要的角色。進一步我們也鑑定出IdeS存在兩大族群 (complex I and II) 且都具備很高的酵素切割活性。此外，已知免疫球蛋白在菌體表面存在兩種結合型式：專一性抗體會經由Fab區域結合抗原；非專一性免疫球蛋白則會經由Fc區域結合在菌體表面的M蛋白或M相似 (M-like) 蛋白。為了釐清IdeS的相對切割能力在此兩種情形中所扮演的角色，我們使用蛋白L (protein L)、蛋白A (protein A) 或M蛋白來代表Fab與Fc結合情形。結果顯示IdeS會快速的切割Fab被結合的IgG，速率和切割游離狀態的IgG相同。相反的，與切割游離狀態的IgG相比，IdeS切割Fc被結合的IgG的速率明顯下降了達4.6倍之多；類似的結果也出現在Fc區域被M蛋白結合時。近來的研究指出IdeS除了會認得要切割的片段外，也需要額外再認得一個結合區域。另外，過去有研究也指出M蛋白對於IgG也具有結合作用。因此，我們推測M蛋白影響IdeS的切割作用是經由和IdeS競爭在IgG上的結合區域。為了證明此一推測，我們利用競爭性結合酶聯免疫吸附法進行實驗，結果顯示M蛋白的確會和IdeS競爭與IgG的結合。由以上結果，我們證實了即使IdeS對於游離態IgG具有高度切割活性，但不可忽視的是對於以不同結合方式呈現的IgG，IdeS的確具有其喜好切割的特性，而此一特性是決定於IgG的Fc區域是否被佔據。此項研究可以幫助我們更加瞭解化膿性鏈球菌逃避IgG媒介之免疫反應的機制。

Streptococcus pyogenes (Group A Streptococcus, GAS) is an important human pathogen capable of causing a wide spectrum of diseases ranging from mild pharyngitis to highly invasive and fatal complications such as necrotizing fasciitis and streptococcal toxic shock syndrome. M protein, which is encoded by the emm gene, is an important virulence factor and is also an epidemiological marker that is used throughout the world to characterize GAS isolates. The emm typing and pulsed-field gel electrophoresis (PFGE) analysis are important surveillance tools to survey and monitor the dynamics in GAS infections. To investigate the changing epidemiology, genetic diversity, and epidemic virulence of GAS infections over a 10-year period in southern Taiwan, a total of 242 isolates recovered from 76 patients with invasive diseases, 89 with scarlet fever, and 77 with pharyngitis were underwent to M genotyping and PFGE analysis. We observed that the most frequent emm types were types 12 (43.4%), 4 (18.2%), and 1 (16.9%). emm12 reemerged in 2005 and peaked in 2007. emm11 was recovered only from patients with invasive disease. To cause the repertoire diseases, a vast assay of virulence factors of GAS participates in the pathogenesis, such as immunoglobulin G (IgG)-degrading enzyme of Streptococcus pyogenes (IdeS) and streptococcal pyrogenic B (SpeB) etc. IdeS is believed to allow GAS to evade the human innate immune response and antibody-mediated phagocytosis by cleaving IgG at the lower hinge region. To better understand the role of IdeS in the pathogenesis of GAS infections, the antibody response to infection and genetic analysis of IdeS variants among 155 of GAS strains were conducted. Patients with invasive GAS infection showed higher antibody levels against IdeS than those with non-invasive infections, though it was not significant higher (P = 0.07). Of invasive subgroup, however, significant lower anti-IdeS antibody levels were found in the patients with severe invasive infection than those with non-severe invasive infections (P = 0.03), showing that IdeS probably played a role for developing severe invasive infection. Further, we identified two major IdeS genetic groups and both exhibited highly endopolypeptidase activity. In addition, immunoglobulins bind to the GAS surface by two well-known mechanisms: specific antibodies attach at the Fab region to their homologous antigens on the bacterial surface or nonspecifically attach at the Fc region to streptococcal M and M-like proteins. To determine the relative ability of IdeS to cleave IgG attached at the Fab or Fc regions, we used Sepharose coated with either protein A or L and M protein as surrogate markers. IdeS cleaved the Fab-bound IgG as rapidly as it degraded IgG in solution. In contrast, Fc-bound IgG was cleaved about 4.6 fold less than soluble IgG. Similar result was found when IgG bound with M protein. Recent researches revealed that the IdeS recognizes the exo-site of IgG other than cleavable site and binds to Fc region of IgG. In addition, the association of M protein to Fc region of IgG has been reported. Therefore, we assumed that influence of M protein in IdeS cleaving rate is through competing with the exo-recognition site of IdeS to the Fc region of IgG. From the competitive binding ELISA, we showed that M protein did compete the binding region of human IgG that bound by IdeS as well. We concluded that even IdeS has highly endopeptidase activity to degrading human IgG in solution; it still exhibited the differential hydrolysis ability to human IgG bound in two different ways. This was caused by competing the binding site of human IgG between Fc-binding proteins and IdeS. This study could help us to better understand GAS escape from IgG-mediated immunity.

Agniswamy, J., Lei, B., Musser, J.M., and Sun, P.D. (2004) Insight of host immune evasion mediated by two variants of Group A Streptococcus Mac protein. J Biol Chem 279: 52789-52796.

Agniswamy, J., Nagiec, M.J., Liu, M., Schuck, P., Musser, J.M., and Sun, P.D. (2006) Crystal structure of Group A Streptococcus Mac-1: insight into dimer-mediated specificity for recognition of human IgG. Structure 14: 225-235.

Akesson, P., Cooney, J., Kishimoto, F., and Bjorck, L. (1990) Protein H--a novel IgG binding bacterial protein. Mol Immunol 27: 523-531.

Åkesson, P., Schmidt, K.H., Cooney, J., and Bjorck, L. (1994) M1 protein and protein H: IgGFc- and albumin-binding streptococcal surface proteins encoded by adjacent genes. Biochem J 300 (Pt 3): 877-886.

Åkesson, P., Rasmussen, M., Mascini, E., von Pawel-Rammingen, U., Janulczyk, R., Collin, M., Olsen, A., Mattsson, E., Olsson, M.L., Bjorck, L., and Christensson, B. (2004) Low antibody levels against cell wall-attached proteins of Streptococcus pyogenes predispose for severe invasive disease. J Infect Dis 189: 797-804.

Åkesson, P., Moritz, L., Truedsson, M., Christensson, B., and von Pawel-Rammingen, U. (2006) IdeS, a highly specific immunoglobulin G (IgG)-cleaving enzyme from Streptococcus pyogenes, is inhibited by specific IgG antibodies generated during infection. Infect Immun 74: 497-503.

Anonymous (1993) Defining the Group A streptococcal toxic shock syndrome. Rationale and consensus definition. The Working Group on Severe Streptococcal Infections. JAMA 269: 390-391.

Anthony, B.F., Yamauchi, T., Penso, J.S., Kamei, I., and Chapman, S.S. (1974) Classroom outbreak of scarlet fever and acute glomerulonephritis related to type 2 (M-2, T-2) Group A Streptococcus. J Infect Dis 129: 336-340.

Auriault, C., Ouaissi, M.A., Torpier, G., Eisen, H., and Capron, A. (1981) Proteolytic cleavage of IgG bound to the Fc receptor of Schistosoma mansoni schistosomula. Parasite Immunol 3: 33-44.

Baker, M., Gutman, D.M., Papageorgiou, A.C., Collins, C.M., and Acharya, K.R. (2001) Structural features of a zinc binding site in the superantigen strepococcal pyrogenic exotoxin A (SpeA1): implications for MHC class II recognition. Protein Sci 10: 1268-1273.

Basma, H., Norrby-Teglund, A., Guedez, Y., McGeer, A., Low, D.E., El-Ahmedy, O., Schwartz, B., and Kotb, M. (1999) Risk factors in the pathogenesis of invasive Group A streptococcal infections: role of protective humoral immunity. Infect Immun 67: 1871-1877.

Beachey, E.H., and Simpson, W.A. (1982) The adherence of Group A streptococci to oropharyngeal cells: the lipoteichoic acid adhesin and fibronectin receptor. Infection 10: 107-111.

Beall, B., Facklam, R., and Thompson, T. (1996) Sequencing emm-specific PCR products for routine and accurate typing of Group A streptococci. J Clin Microbiol 34: 953-958.

Berge, A., and Bjorck, L. (1995) Streptococcal cysteine proteinase releases biologically active fragments of streptococcal surface proteins. J Biol Chem 270: 9862-9867.

Berge, A., Kihlberg, B.M., Sjoholm, A.G., and Bjorck, L. (1997) Streptococcal protein H forms soluble complement-activating complexes with IgG, but inhibits complement activation by IgG-coated targets. J Biol Chem 272: 20774-20781.

Berggard, K., Johnsson, E., Morfeldt, E., Persson, J., Stalhammar-Carlemalm, M., and Lindahl, G. (2001) Binding of human C4BP to the hypervariable region of M protein: a molecular mechanism of phagocytosis resistance in Streptococcus pyogenes. Mol Microbiol 42: 539-551.

Berkower, C., Ravins, M., Moses, A.E., and Hanski, E. (1999) Expression of different Group A streptococcal M proteins in an isogenic background demonstrates diversity in adherence to and invasion of eukaryotic cells. Mol Microbiol 31: 1463-1475.

Bessen, D., Jones, K.F., and Fischetti, V.A. (1989) Evidence for two distinct classes of streptococcal M protein and their relationship to rheumatic fever. J Exp Med 169: 269-283.

Bessen, D.E., and Fischetti, V.A. (1990) Differentiation between two biologically distinct classes of Group A streptococci by limited substitutions of amino acids within the shared region of M protein-like molecules. J Exp Med 172: 1757-1764.

Bessen, D.E., and Fischetti, V.A. (1992) Nucleotide sequences of two adjacent M or M-like protein genes of Group A streptococci: different RNA transcript levels and identification of a unique immunoglobulin A-binding protein. Infect Immun 60: 124-135.

Bessen, D.E. (1994) Localization of immunoglobulin A-binding sites within M or M-like proteins of Group A streptococci. Infect Immun 62: 1968-1974.

Bessen, D.E., Veasy, L.G., Hill, H.R., Augustine, N.H., and Fischetti, V.A. (1995) Serologic evidence for a class I Group A streptococcal infection among rheumatic fever patients. J Infect Dis 172: 1608-1611.

Bessen, D.E., Izzo, M.W., Fiorentino, T.R., Caringal, R.M., Hollingshead, S.K., and Beall, B. (1999) Genetic linkage of exotoxin alleles and emm gene markers for tissue tropism in Group A streptococci. J Infect Dis 179: 627-636.

Bessen, D.E., Carapetis, J.R., Beall, B., Katz, R., Hibble, M., Currie, B.J., Collingridge, T., Izzo, M.W., Scaramuzzino, D.A., and Sriprakash, K.S. (2000) Contrasting molecular epidemiology of Group A streptococci causing tropical and nontropical infections of the skin and throat. J Infect Dis 182: 1109-1116.

Bisno, A.L., Brito, M.O., and Collins, C.M. (2003) Molecular basis of Group A streptococcal virulence. Lancet Infect Dis 3: 191-200.

Bjorck, L., and Kronvall, G. (1984) Purification and some properties of streptococcal protein G, a novel IgG-binding reagent. J Immunol 133: 969-974.

Bjorck, L. (1988) Protein L. A novel bacterial cell wall protein with affinity for Ig L chains. J Immunol 140: 1194-1197.

Blankenfeldt, W., Thoma, N.H., Wray, J.S., Gautel, M., and Schlichting, I. (2006) Crystal structures of human cardiac beta-myosin II S2-Delta provide insight into the functional role of the S2 subfragment. Proc Natl Acad Sci USA 103: 17713-17717.

Boyle, M.D., Hawlitzky, J., Raeder, R., and Podbielski, A. (1994) Analysis of genes encoding two unique type IIa immunoglobulin G-binding proteins expressed by a single Group A streptococcal isolate. Infect Immun 62: 1336-1347.

Boyle, M.D., Weber-Heynemann, J., Raeder, R., and Podbielski, A. (1995) Characterization of a gene coding for a type IIo bacterial IgG-binding protein. Mol Immunol 32: 669-678.

Boyum, A. (1968) Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl 97: 77-89.

Brown, J.H., Kim, K.H., Jun, G., Greenfield, N.J., Dominguez, R., Volkmann, N., Hitchcock-DeGregori, S.E., and Cohen, C. (2001) Deciphering the design of the tropomyosin molecule. Proc Natl Acad Sci USA 98: 8496-8501.

Brown, J.H., Zhou, Z., Reshetnikova, L., Robinson, H., Yammani, R.D., Tobacman, L.S., and Cohen, C. (2005) Structure of the mid-region of tropomyosin: bending and binding sites for actin. Proc Natl Acad Sci USA 102: 18878-18883.

Caparon, M.G., Geist, R.T., Perez-Casal, J., and Scott, J.R. (1992) Environmental regulation of virulence in Group A streptococci: transcription of the gene encoding M protein is stimulated by carbon dioxide. J Bacteriol 174: 5693-5701.

Carapetis, J., Gardiner, D., Currie, B., and Mathews, J.D. (1995) Multiple strains of Streptococcus pyogenes in skin sores of aboriginal Australians. J Clin Microbiol 33: 1471-1472.

Carapetis, J.R., Steer, A.C., Mulholland, E.K., and Weber, M. (2005) The global burden of Group A streptococcal diseases. Lancet Infect Dis 5: 685-694.

Carlsson, F., Berggard, K., Stalhammar-Carlemalm, M., and Lindahl, G. (2003) Evasion of phagocytosis through cooperation between two ligand-binding regions in Streptococcus pyogenes M protein. J Exp Med 198: 1057-1068.

Carlsson, F., Sandin, C., and Lindahl, G. (2005) Human fibrinogen bound to Streptococcus pyogenes M protein inhibits complement deposition via the classical pathway. Mol Microbiol 56: 28-39.

Centers for Disease Control, Department of Health, Execultive Yuan, Taiwan (1996) Flesh-Eating Bacteria: Current Status of Group A streptococcal Infectious Gangrene in Taiwan. Epidemiol Bull 12: 105-114.

Cerenius, L., Bangyeekhun, E., Keyser, P., Soderhall, I., and Soderhall, K. (2003) Host prophenoloxidase expression in freshwater crayfish is linked to increased resistance to the crayfish plague fungus, Aphanomyces astaci. Cell Microbiol 5: 353-357.

Chen, W.Y. (2006) Characterization of immunoglobulin G degrading enzyme and screening the cellular interaction proteins with oligopeptide permease A in Group A Streptococcus. M.S. Thesis, Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng-Kung University.

Chen, Y.Y., Huang, C.T., Yao, S.M., Chang, Y.C., Shen, P.W., Chou, C.Y., and Li, S.Y. (2007) Molecular epidemiology of Group A Streptococcus causing scarlet fever in northern Taiwan, 2001-2002. Diagn Microbiol Infect Dis 58: 289-295.

Chi, J.C. (2005) Expression and Characterization of IdeS, an IgG-degrading protease of Streptococcus pyogenes. M.S. Thesis, Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng-Kung University.

Chiang-Ni, C., and Wu, J.J. (2008) Effects of streptococcal pyrogenic exotoxin B on pathogenesis of Streptococcus pyogenes. J Formos Med Assoc 107: 677-685.

Chiou, C.S., Liao, T.L., Wang, T.H., Chang, H.L., Liao, J.C., and Li, C.C. (2004) Epidemiology and molecular characterization of Streptococcus pyogenes recovered from scarlet fever patients in central Taiwan from 1996 to 1999. J Clin Microbiol 42: 3998-4006.

Chuang, I., Van Beneden, C., Beall, B., and Schuchat, A. (2002) Population-based surveillance for postpartum invasive Group A Streptococcus infections, 1995-2000. Clin Infect Dis 35: 665-670.

Chung, Y.B., Yang, H.J., Kang, S.Y., Kong, Y., and Cho, S.Y. (1997) Activities of different cysteine proteases of Paragonimus westermani in cleaving human IgG. Korean J Parasitol 35: 139-142.

Colman, G., Tanna, A., Efstratiou, A., and Gaworzewska, E.T. (1993) The serotypes of Streptococcus pyogenes present in Britain during 1980-1990 and their association with disease. J Med Microbiol 39: 165-178.

Cone, L.A., Woodard, D.R., Schlievert, P.M., and Tomory, G.S. (1987) Clinical and bacteriologic observations of a toxic shock-like syndrome due to Streptococcus pyogenes. N Engl J Med 317: 146-149.

Courtney, H.S., von Hunolstein, C., Dale, J.B., Bronze, M.S., Beachey, E.H., and Hasty, D.L. (1992) Lipoteichoic acid and M protein: dual adhesins of Group A streptococci. Microb Pathog 12: 199-208.

Cu, G.A., Mezzano, S., Bannan, J.D., and Zabriskie, J.B. (1998) Immunohistochemical and serological evidence for the role of streptococcal proteinase in acute post-streptococcal glomerulonephritis. Kidney Int 54: 819-826.

Cue, D., Dombek, P.E., Lam, H., and Cleary, P.P. (1998) Streptococcus pyogenes serotype M1 encodes multiple pathways for entry into human epithelial cells. Infect Immun 66: 4593-4601.

Cue, D., Lam, H., and Cleary, P.P. (2001) Genetic dissection of the Streptococcus pyogenes M1 protein: regions involved in fibronectin binding and intracellular invasion. Microb Pathog 31: 231-242.

Cunningham, M.W. (2000) Pathogenesis of Group A streptococcal infections. Clin Microbiol Rev 13: 470-511.

Dale, J.B., Washburn, R.G., Marques, M.B., and Wessels, M.R. (1996) Hyaluronate capsule and surface M protein in resistance to opsonization of Group A streptococci. Infect Immun 64: 1495-1501.

Dale, J.B., Chiang, E.Y., Hasty, D.L., and Courtney, H.S. (2002) Antibodies against a synthetic peptide of SagA neutralize the cytolytic activity of streptolysin S from Group A streptococci. Infect Immun 70: 2166-2170.

Dombek, P.E., Cue, D., Sedgewick, J., Lam, H., Ruschkowski, S., Finlay, B.B., and Cleary, P.P. (1999) High-frequency intracellular invasion of epithelial cells by serotype M1 Group A streptococci: M1 protein-mediated invasion and cytoskeletal rearrangements. Mol Microbiol 31: 859-870.

Eisen, H., and Tallan, I. (1977) Tetrahymena pyriformis recovers from antibody immobilisation by producing univalent antibody fragments. Nature 270: 514-515.

Ellen, R.P., and Gibbons, R.J. (1972) M protein-associated adherence of Streptococcus pyogenes to epithelial surfaces: prerequisite for virulence. Infect Immun 5: 826-830.

Ellen, R.P., and Gibbons, R.J. (1974) Parameters affecting the adherence and tissue tropisms of Streptococcus pyogenes. Infect Immun 9: 85-91.

Eriksson, A., and Norgren, M. (2003) Cleavage of antigen-bound immunoglobulin G by SpeB contributes to streptococcal persistence in opsonizing blood. Infect Immun 71: 211-217.

Facklam, R., Beall, B., Efstratiou, A., Fischetti, V., Johnson, D., Kaplan, E., Kriz, P., Lovgren, M., Martin, D., Schwartz, B., Totolian, A., Bessen, D., Hollingshead, S., Rubin, F., Scott, J., and Tyrrell, G. (1999) emm typing and validation of provisional M types for Group A streptococci. Emerg Infect Dis 5: 247-253.

Facklam, R.F., Martin, D.R., Lovgren, M., Johnson, D.R., Efstratiou, A., Thompson, T.A., Gowan, S., Kriz, P., Tyrrell, G.J., Kaplan, E., and Beall, B. (2002) Extension of the Lancefield classification for Group A streptococci by addition of 22 new M protein gene sequence types from clinical isolates: emm103 to emm124. Clin Infect Dis 34: 28-38.

Feito, M.J., Sanchez, A., Oliver, M.A., Perez-Caballero, D., Rodriguez de Cordoba, S., Alberti, S., and Rojo, J.M. (2007) Membrane cofactor protein (MCP, CD46) binding to clinical isolates of Streptococcus pyogenes: binding to M type 18 strains is independent of Emm or Enn proteins. Mol Immunol 44: 3571-3579.

Fernie-King, B.A., Seilly, D.J., Davies, A., and Lachmann, P.J. (2002) Streptococcal inhibitor of complement inhibits two additional components of the mucosal innate immune system: secretory leukocyte proteinase inhibitor and lysozyme. Infect Immun 70: 4908-4916.

Fischetti, V.A. (1989) Streptococcal M protein: molecular design and biological behavior. Clin Microbiol Rev 2: 285-314.

Fischetti, V.A. (1991) Streptococcal M protein. Sci Am 264: 58-65.

Fischetti, V.A., Horstmann, R.D., and Pancholi, V. (1995) Location of the complement factor H binding site on streptococcal M6 protein. Infect Immun 63: 149-153.

Forsgren, A., and Sjoquist, J. (1966) "Protein A" from S. aureus. I. Pseudo-immune reaction with human gamma-globulin. J Immunol 97: 822-827.

Frick, I.M., Akesson, P., Cooney, J., Sjobring, U., Schmidt, K.H., Gomi, H., Hattori, S., Tagawa, C., Kishimoto, F., and Bjorck, L. (1994) Protein H--a surface protein of Streptococcus pyogenes with separate binding sites for IgG and albumin. Mol Microbiol 12: 143-151.

Frick, I.M., Schmidtchen, A., and Sjobring, U. (2003) Interactions between M proteins of Streptococcus pyogenes and glycosaminoglycans promote bacterial adhesion to host cells. Eur J Biochem 270: 2303-2311.

Gautom, R.K. (1997) Rapid pulsed-field gel electrophoresis protocol for typing of Escherichia coli O157:H7 and other gram-negative organisms in 1 day. J Clin Microbiol 35: 2977-2980.

Giannakis, E., Jokiranta, T.S., Ormsby, R.J., Duthy, T.G., Male, D.A., Christiansen, D., Fischetti, V.A., Bagley, C., Loveland, B.E., and Gordon, D.L. (2002) Identification of the streptococcal M protein binding site on membrane cofactor protein (CD46). J Immunol 168: 4585-4592.

Gold, P.C., and Johnson, J.A. (1982) Prediction of achievement in reading, self-esteem, auding, and verbal language by adult illiterates in a psychoeducational tutorial program. J Clin Psychol 38: 513-522.

Gomi, H., Hozumi, T., Hattori, S., Tagawa, C., Kishimoto, F., and Bjorck, L. (1990) The gene sequence and some properties of protein H. A novel IgG-binding protein. J Immunol 144: 4046-4052.

Greco, R., De Martino, L., Donnarumma, G., Conte, M.P., Seganti, L., and Valenti, P. (1995) Invasion of cultured human cells by Streptococcus pyogenes. Res Microbiol 146: 551-560.

Green, N.M., Zhang, S., Porcella, S.F., Nagiec, M.J., Barbian, K.D., Beres, S.B., LeFebvre, R.B., and Musser, J.M. (2005) Genome sequence of a serotype M28 strain of Group A Streptococcus: potential new insights into puerperal sepsis and bacterial disease specificity. J Infect Dis 192: 760-770.

Greenfield, N.J., Huang, Y.J., Swapna, G.V., Bhattacharya, A., Rapp, B., Singh, A., Montelione, G.T., and Hitchcock-DeGregori, S.E. (2006) Solution NMR structure of the junction between tropomyosin molecules: implications for actin binding and regulation. J Mol Biol 364: 80-96.

Hagman, M.M., Dale, J.B., and Stevens, D.L. (1999) Comparison of adherence to and penetration of a human laryngeal epithelial cell line by Group A streptococci of various M protein types. FEMS Immunol Med Microbiol 23: 195-204.

Hanski, E., and Caparon, M. (1992) Protein F, a fibronectin-binding protein, is an adhesin of the Group A Streptococcus Streptococcus pyogenes. Proc Natl Acad Sci USA 89: 6172-6176.

Holder, I.A., and Wheeler, R. (1984) Experimental studies of the pathogenesis of infections owing to Pseudomonas aeruginosa: elastase, an IgG protease. Can J Microbiol 30: 1118-1124.

Hollingshead, S.K., Fischetti, V.A., and Scott, J.R. (1987) A highly conserved region present in transcripts encoding heterologous M proteins of Group A streptococci. Infect Immun 55: 3237-3239.

Horstmann, R.D., Sievertsen, H.J., Knobloch, J., and Fischetti, V.A. (1988) Antiphagocytic activity of streptococcal M protein: selective binding of complement control protein factor H. Proc Natl Acad Sci USA 85: 1657-1661.

Horstmann, R.D., Sievertsen, H.J., Leippe, M., and Fischetti, V.A. (1992) Role of fibrinogen in complement inhibition by streptococcal M protein. Infect Immun 60: 5036-5041.

Hribalova, V. (1988) Streptococcus pyogenes and the toxic shock syndrome. Ann Intern Med 108: 772.

Hsueh, P.R., Teng, L.J., Lee, P.I., Yang, P.C., Huang, L.M., Chang, S.C., Lee, C.Y., and Luh, K.T. (1997) Outbreak of scarlet fever at a hospital day care centre: analysis of strain relatedness with phenotypic and genotypic characteristics. J Hosp Infect 36: 191-200.

Hu, M.C., Walls, M.A., Stroop, S.D., Reddish, M.A., Beall, B., and Dale, J.B. (2002) Immunogenicity of a 26-valent Group A streptococcal vaccine. Infect Immun 70: 2171-2177.

Jansen, H.J., Grenier, D., and Van der Hoeven, J.S. (1995) Characterization of immunoglobulin G-degrading proteases of Prevotella intermedia and Prevotella nigrescens. Oral Microbiol Immunol 10: 138-145.

Ji, Y., McLandsborough, L., Kondagunta, A., and Cleary, P.P. (1996) C5a peptidase alters clearance and trafficking of Group A streptococci by infected mice. Infect Immun 64: 503-510.

Johansson, B.P., Shannon, O., and Bjorck, L. (2008) IdeS: a bacterial proteolytic enzyme with therapeutic potential. PLoS ONE 3: e1692.

Johnsson, E., Thern, A., Dahlback, B., Heden, L.O., Wikstrom, M., and Lindahl, G. (1996) A highly variable region in members of the streptococcal M protein family binds the human complement regulator C4BP. J Immunol 157: 3021-3029.

Johnsson, E., Berggard, K., Kotarsky, H., Hellwage, J., Zipfel, P.F., Sjobring, U., and Lindahl, G. (1998) Role of the hypervariable region in streptococcal M proteins: binding of a human complement inhibitor. J Immunol 161: 4894-4901.

Kao, C.H., Chen, P.Y., Huang, F.L., Chen, C.W., Chi, C.S., Lin, Y.H., Shih, C.Y., Hu, B.S., Li, C.R., Ma, J.S., Lau, Y.J., Lu, K.C., and Yu, H.W. (2005) Clinical and genetic analysis of invasive and non-invasive Group A streptococcal infections in central Taiwan. J Microbiol Immunol Infect 38: 105-111.

Kaplan, E.L., Johnson, D.R., and Cleary, P.P. (1989) Group A streptococcal serotypes isolated from patients and sibling contacts during the resurgence of rheumatic fever in the United States in the mid-1980s. J Infect Dis 159: 101-103.

Kaplan, E.L., Wotton, J.T., and Johnson, D.R. (2001) Dynamic epidemiology of Group A streptococcal serotypes associated with pharyngitis. Lancet 358: 1334-1337.

Kawabata, S., Tamura, Y., Murakami, J., Terao, Y., Nakagawa, I., and Hamada, S. (2002) A novel, anchorless streptococcal surface protein that binds to human immunoglobulins. Biochem Biophys Res Commun 296: 1329-1333.

Kihlberg, B.M., Collin, M., Olsen, A., and Bjorck, L. (1999) Protein H, an antiphagocytic surface protein in Streptococcus pyogenes. Infect Immun 67: 1708-1714.

Kohler, W., Gerlach, D., and Knoll, H. (1987) Streptococcal outbreaks and erythrogenic toxin type A. Zentralbl Bakteriol Mikrobiol Hyg 266: 104-115.

Kotarsky, H., Hellwage, J., Johnsson, E., Skerka, C., Svensson, H.G., Lindahl, G., Sjobring, U., and Zipfel, P.F. (1998) Identification of a domain in human factor H and factor H-like protein-1 required for the interaction with streptococcal M proteins. J Immunol 160: 3349-3354.

Kronvall, G. (1973) A surface component in Group A, C, and G streptococci with non-immune reactivity for immunoglobulin G. J Immunol 111: 1401-1406.

Lancefield, R.C. (1962) Current knowledge of type-specific M antigens of Group A streptococci. J Immunol 89: 307-313.

LaPenta, D., Rubens, C., Chi, E., and Cleary, P.P. (1994) Group A streptococci efficiently invade human respiratory epithelial cells. Proc Natl Acad Sci USA 91: 12115-12119.

Lei, B., Mackie, S., Lukomski, S., and Musser, J.M. (2000) Identification and immunogenicity of Group A Streptococcus culture supernatant proteins. Infect Immun 68: 6807-6818.

Lei, B., DeLeo, F.R., Hoe, N.P., Graham, M.R., Mackie, S.M., Cole, R.L., Liu, M., Hill, H.R., Low, D.E., Federle, M.J., Scott, J.R., and Musser, J.M. (2001) Evasion of human innate and acquired immunity by a bacterial homolog of CD11b that inhibits opsonophagocytosis. Nat Med 7: 1298-1305.

Lei, B., DeLeo, F.R., Reid, S.D., Voyich, J.M., Magoun, L., Liu, M., Braughton, K.R., Ricklefs, S., Hoe, N.P., Cole, R.L., Leong, J.M., and Musser, J.M. (2002) Opsonophagocytosis-inhibiting mac protein of Group A Streptococcus: identification and characteristics of two genetic complexes. Infect Immun 70: 6880-6890.

Lei, B., Liu, M., Meyers, E.G., Manning, H.M., Nagiec, M.J., and Musser, J.M. (2003) Histidine and aspartic acid residues important for immunoglobulin G endopeptidase activity of the Group A Streptococcus opsonophagocytosis-inhibiting Mac protein. Infect Immun 71: 2881-2884.

Li, Y., Mui, S., Brown, J.H., Strand, J., Reshetnikova, L., Tobacman, L.S., and Cohen, C. (2002) The crystal structure of the C-terminal fragment of striated-muscle alpha-tropomyosin reveals a key troponin T recognition site. Proc Natl Acad Sci USA 99: 7378-7383.

Li, Y., Brown, J.H., Reshetnikova, L., Blazsek, A., Farkas, L., Nyitray, L., and Cohen, C. (2003) Visualization of an unstable coiled coil from the scallop myosin rod. Nature 424: 341-345.

Lindahl, G., and Stenberg, L. (1990) Binding of IgA and/or IgG is a common property among clinical isolates of Group A streptococci. Epidemiol Infect 105: 87-93.
Madden, J.C., Ruiz, N., and Caparon, M. (2001) Cytolysin-mediated translocation (CMT): a functional equivalent of type III secretion in gram-positive bacteria. Cell 104: 143-152.

Mascini, E.M., Jansze, M., Schellekens, J.F., Musser, J.M., Faber, J.A., Verhoef-Verhage, L.A., Schouls, L., van Leeuwen, W.J., Verhoef, J., and van Dijk, H. (2000) Invasive Group A streptococcal disease in the Netherlands: evidence for a protective role of anti-exotoxin A antibodies. J Infect Dis 181: 631-638.

Massell, B.F., Honikman, L.H., and Amezcua, J. (1969) Rheumatic fever following streptococcal vaccination. Report of three cases. JAMA 207: 1115-1119.

McNamara, C., Zinkernagel, A.S., Macheboeuf, P., Cunningham, M.W., Nizet, V., and Ghosh, P. (2008) Coiled-coil irregularities and instabilities in Group A Streptococcus M1 are required for virulence. Science 319: 1405-1408.

Medina, E., Molinari, G., Rohde, M., Haase, B., Chhatwal, G.S., and Guzman, C.A. (1999) Fc-mediated nonspecific binding between fibronectin-binding protein I of Streptococcus pyogenes and human immunoglobulins. J Immunol 163: 3396-3402.

Molinari, G., Talay, S.R., Valentin-Weigand, P., Rohde, M., and Chhatwal, G.S. (1997) The fibronectin-binding protein of Streptococcus pyogenes, SfbI, is involved in the internalization of Group A streptococci by epithelial cells. Infect Immun 65: 1357-1363.

Molinari, G., and Chhatwal, G.S. (1998) Invasion and survival of Streptococcus pyogenes in eukaryotic cells correlates with the source of the clinical isolates. J Infect Dis 177: 1600-1607.

Molinari, G., and Chhatwal, G.S. (1999) Role played by the fibronectin-binding protein SfbI (Protein F1) of Streptococcus pyogenes in bacterial internalization by epithelial cells. J Infect Dis 179: 1049-1050.

Molla, A., Kagimoto, T., and Maeda, H. (1988) Cleavage of immunoglobulin G (IgG) and IgA around the hinge region by proteases from Serratia marcescens. Infect Immun 56: 916-920.

Montes, M., Orden, B., Tamayo, E., Alos, J.I., and Perez-Trallero, E. (2006) Characterisation of the main clones of Streptococcus pyogenes carrying the ermA (subclass TR) gene in Spain. Int J Antimicrob Agents 28: 408-412.

Morfeldt, E., Berggard, K., Persson, J., Drakenberg, T., Johnsson, E., Lindahl, E., Linse, S., and Lindahl, G. (2001) Isolated hypervariable regions derived from streptococcal M proteins specifically bind human C4b-binding protein: implications for antigenic variation. J Immunol 167: 3870-3877.

Musser, J.M., Nelson, K., Selander, R.K., Gerlach, D., Huang, J.C., Kapur, V., and Kanjilal, S. (1993) Temporal variation in bacterial disease frequency: molecular population genetic analysis of scarlet fever epidemics in Ottawa and in eastern Germany. J Infect Dis 167: 759-762.

Mylvaganam, H., Bjorvatn, B., and Osland, A. (2000) Distribution and sequence variations of selected virulence genes among Group A streptococcal isolates from western Norway. APMIS 108: 771-778.

Nandakumar, K.S., Johansson, B.P., Bjorck, L., and Holmdahl, R. (2007) Blocking of experimental arthritis by cleavage of IgG antibodies in vivo. Arthritis Rheum 56: 3253-3260.

Navarre, W.W., and Schneewind, O. (1999) Surface proteins of gram-positive bacteria and mechanisms of their targeting to the cell wall envelope. Microbiol Mol Biol Rev 63: 174-229.

Nilson, B.H., Solomon, A., Bjorck, L., and Akerstrom, B. (1992) Protein L from Peptostreptococcus magnus binds to the kappa light chain variable domain. J Biol Chem 267: 2234-2239.

Nobbs, A.H., Lamont, R.J., and Jenkinson, H.F. (2009) Streptococcus adherence and colonization. Microbiol Mol Biol Rev 73: 407-450.

Nordstrand, A., Norgren, M., Ferretti, J.J., and Holm, S.E. (1998) Streptokinase as a mediator of acute post-streptococcal glomerulonephritis in an experimental mouse model. Infect Immun 66: 315-321.

Nordstrand, A., Norgren, M., and Holm, S.E. (1999) Pathogenic mechanism of acute post-streptococcal glomerulonephritis. Scand J Infect Dis 31: 523-537.

O'Brien, K.L., Beall, B., Barrett, N.L., Cieslak, P.R., Reingold, A., Farley, M.M., Danila, R., Zell, E.R., Facklam, R., Schwartz, B., and Schuchat, A. (2002) Epidemiology of invasive Group A Streptococcus disease in the United States, 1995-1999. Clin Infect Dis 35: 268-276.

O'Loughlin, R.E., Roberson, A., Cieslak, P.R., Lynfield, R., Gershman, K., Craig, A., Albanese, B.A., Farley, M.M., Barrett, N.L., Spina, N.L., Beall, B., Harrison, L.H., Reingold, A., and Van Beneden, C. (2007) The epidemiology of invasive Group A streptococcal infection and potential vaccine implications: United States, 2000-2004. Clin Infect Dis 45: 853-862.

O'Toole, P.W., Stenberg, L., Rissler, M., and Lindahl, G. (1992) Two major classes in the M protein family in Group A streptococci. Proc Natl Acad Sci USA 89: 8661-8665.

Oehmcke, S., Shannon, O., Morgelin, M., and Herwald, H. (2010) Streptococcal M proteins and their role as virulence determinants. Clin Chim Acta 411: 1172-1180.

Ohga, S., Okada, K., Mitsui, K., Aoki, T., and Ueda, K. (1992) Outbreaks of Group A beta-hemolytic streptococcal pharyngitis in children: correlation of serotype T4 with scarlet fever. Scand J Infect Dis 24: 599-605.

Okada, N., Liszewski, M.K., Atkinson, J.P., and Caparon, M. (1995) Membrane cofactor protein (CD46) is a keratinocyte receptor for the M protein of the Group A Streptococcus. Proc Natl Acad Sci USA 92: 2489-2493.

Osterlund, A., and Engstrand, L. (1995) Intracellular penetration and survival of Streptococcus pyogenes in respiratory epithelial cells in vitro. Acta Otolaryngol 115: 685-688.

Osterlund, A., and Engstrand, L. (1997) An intracellular sanctuary for Streptococcus pyogenes in human tonsillar epithelium--studies of asymptomatic carriers and in vitro cultured biopsies. Acta Otolaryngol 117: 883-888.

Ozeri, V., Rosenshine, I., Mosher, D.F., Fassler, R., and Hanski, E. (1998) Roles of integrins and fibronectin in the entry of Streptococcus pyogenes into cells via protein F1. Mol Microbiol 30: 625-637.

Parker, M.T. (1967) International survey of the distribution of serotypes of Streptococcus pyogenes (Group A streptococci). Bull World Health Organ 37: 513-527.

Perea-Mejia, L.M., Inzunza-Montiel, A.E., and Cravioto, A. (2002) Molecular characterization of Group A Streptococcus strains isolated during a scarlet fever outbreak. J Clin Microbiol 40: 278-280.

Perez-Casal, J., Caparon, M.G., and Scott, J.R. (1992) Introduction of the emm6 gene into an emm-deleted strain of Streptococcus pyogenes restores its ability to resist phagocytosis. Res Microbiol 143: 549-558.

Perez-Casal, J., Okada, N., Caparon, M.G., and Scott, J.R. (1995) Role of the conserved C-repeat region of the M protein of Streptococcus pyogenes. Mol Microbiol 15: 907-916.

Perks, E.M., and Mayon-White, R.T. (1983) The incidence of scarlet fever. J Hyg (London) 91: 203-209.

Podbielski, A., Beckert, S., Schattke, R., Leithauser, F., Lestin, F., Gossler, B., and Kreikemeyer, B. (2003) Epidemiology and virulence gene expression of intracellular Group A streptococci in tonsils of recurrently infected adults. Int J Med Microbiol 293: 179-190.

Purushothaman, S.S., Wang, B., and Cleary, P.P. (2003) M1 protein triggers a phosphoinositide cascade for Group A Streptococcus invasion of epithelial cells. Infect Immun 71: 5823-5830.

Raeder, R., and Boyle, M.D. (1993) Association between expression of immunoglobulin G-binding proteins by Group A streptococci and virulence in a mouse skin infection model. Infect Immun 61: 1378-1384.

Reis, K.J., Ayoub, E.M., and Boyle, M.D. (1984) Streptococcal Fc receptors. I. Isolation and partial characterization of the receptor from a group C streptococcus. J Immunol 132: 3091-3097.

Retnoningrum, D.S., and Cleary, P.P. (1994) M12 protein from Streptococcus pyogenes is a receptor for immunoglobulin G3 and human albumin. Infect Immun 62: 2387-2394.

Rezcallah, M.S., Hodges, K., Gill, D.B., Atkinson, J.P., Wang, B., and Cleary, P.P. (2005) Engagement of CD46 and alpha5beta1 integrin by Group A streptococci is required for efficient invasion of epithelial cells. Cell Microbiol 7: 645-653.

Sandin, C., Carlsson, F., and Lindahl, G. (2006) Binding of human plasma proteins to Streptococcus pyogenes M protein determines the location of opsonic and non-opsonic epitopes. Mol Microbiol 59: 20-30.

Sanford, B.A., Davison, V.E., and Ramsay, M.A. (1982) Fibrinogen-mediated adherence of Group A Streptococcus to influenza A virus-infected cell cultures. Infect Immun 38: 513-520.

Saravani, G.A., and Martin, D.R. (1990a) Opacity factor from Group A streptococci is an apoproteinase. FEMS Microbiol Lett 56: 35-39.

Saravani, G.A., and Martin, D.R. (1990b) Characterisation of opacity factor from group-A streptococci. J Med Microbiol 33: 55-60.

Schmidt, K.H., Mann, K., Cooney, J., and Kohler, W. (1993) Multiple binding of type 3 streptococcal M protein to human fibrinogen, albumin and fibronectin. FEMS Immunol Med Microbiol 7: 135-143.

Sharkawy, A., Low, D.E., Saginur, R., Gregson, D., Schwartz, B., Jessamine, P., Green, K., and McGeer, A. (2002) Severe Group A streptococcal soft-tissue infections in Ontario: 1992-1996. Clin Infect Dis 34: 454-460.

Shin, M.H., Kita, H., Park, H.Y., and Seoh, J.Y. (2001) Cysteine protease secreted by Paragonimus westermani attenuates effector functions of human eosinophils stimulated with immunoglobulin G. Infect Immun 69: 1599-1604.

Smeesters, P.R., Vergison, A., Campos, D., de Aguiar, E., Miendje Deyi, V.Y., and Van Melderen, L. (2006) Differences between Belgian and Brazilian Group A Streptococcus epidemiologic landscape. PLoS One 1: e10.

Smeesters, P.R., McMillan, D.J., and Sriprakash, K.S. (2010) The streptococcal M protein: a highly versatile molecule. Trends Microbiol 18: 275-282.

Söderberg, J.J., Engstrom, P., and von Pawel-Rammingen, U. (2008) The intrinsic immunoglobulin G endopeptidase activity of streptococcal Mac-2 proteins implies a unique role for the enzymatically impaired Mac-2 protein of M28 serotype strains. Infect Immun 76: 2183-2188.

Söderberg, J.J., and von Pawel-Rammingen, U. (2008) The streptococcal protease IdeS modulates bacterial IgGFc binding and generates 1/2Fc fragments with the ability to prime polymorphonuclear leucocytes. Mol Immunol 45: 3347-3353.

Stenberg, L., O'Toole, P., and Lindahl, G. (1992) Many Group A streptococcal strains express two different immunoglobulin-binding proteins, encoded by closely linked genes: characterization of the proteins expressed by four strains of different M-type. Mol Microbiol 6: 1185-1194.

Stenberg, L., O'Toole, P.W., Mestecky, J., and Lindahl, G. (1994) Molecular characterization of protein Sir, a streptococcal cell surface protein that binds both immunoglobulin A and immunoglobulin G. J Biol Chem 269: 13458-13464.

Stevens, D.L., Tanner, M.H., Winship, J., Swarts, R., Ries, K.M., Schlievert, P.M., and Kaplan, E. (1989) Severe Group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A. N Engl J Med 321: 1-7.

Stevens, D.L. (1992) Invasive Group A Streptococcus infections. Clin Infect Dis 14: 2-11.

Stockbauer, K.E., Magoun, L., Liu, M., Burns, E.H., Jr., Gubba, S., Renish, S., Pan, X., Bodary, S.C., Baker, E., Coburn, J., Leong, J.M., and Musser, J.M. (1999) A natural variant of the cysteine protease virulence factor of Group A Streptococcus with an arginine-glycine-aspartic acid (RGD) motif preferentially binds human integrins alphavbeta3 and alphaIIbbeta3. Proc Natl Acad Sci USA 96: 242-247.

Su, Y.F., Wang, S.M., Lin, Y.L., Chuang, W.J., Lin, Y.S., Wu, J.J., Lin, M.T., and Liu, C.C. (2009) Changing epidemiology of Streptococcus pyogenes emm types and associated invasive and noninvasive infections in southern Taiwan. J Clin Microbiol 47: 2658-2661.

Tewodros, W., and Kronvall, G. (2005) M protein gene (emm type) analysis of Group A beta-hemolytic streptococci from Ethiopia reveals unique patterns. J Clin Microbiol 43: 4369-4376.

Thern, A., Stenberg, L., Dahlback, B., and Lindahl, G. (1995) Ig-binding surface proteins of Streptococcus pyogenes also bind human C4b-binding protein (C4BP), a regulatory component of the complement system. J Immunol 154: 375-386.

Thern, A., Wastfelt, M., and Lindahl, G. (1998) Expression of two different antiphagocytic M proteins by Streptococcus pyogenes of the OF+ lineage. J Immunol 160: 860-869.

Thigpen, M.C., Thomas, D.M., Gloss, D., Park, S.Y., Khan, A.J., Fogelman, V.L., Beall, B., Van Beneden, C.A., Todd, R.L., and Greene, C.M. (2007) Nursing home outbreak of invasive Group A streptococcal infections caused by 2 distinct strains. Infect Control Hosp Epidemiol 28: 68-74.

Veasy, L.G., Tani, L.Y., Daly, J.A., Korgenski, K., Miner, L., Bale, J., Kaplan, E.L., Musser, J.M., and Hill, H.R. (2004) Temporal association of the appearance of mucoid strains of Streptococcus pyogenes with a continuing high incidence of rheumatic fever in Utah. Pediatrics 113: e168-172.

Vincents, B., von Pawel-Rammingen, U., Bjorck, L., and Abrahamson, M. (2004) Enzymatic characterization of the streptococcal endopeptidase, IdeS, reveals that it is a cysteine protease with strict specificity for IgG cleavage due to exosite binding. Biochemistry 43: 15540-15549.

Vincents, B., Vindebro, R., Abrahamson, M., and von Pawel-Rammingen, U. (2008) The human protease inhibitor cystatin C is an activating cofactor for the streptococcal cysteine protease IdeS. Chem Biol 15: 960-968.

von Pawel-Rammingen, U., Johansson, B.P., and Bjorck, L. (2002) IdeS, a novel streptococcal cysteine proteinase with unique specificity for immunoglobulin G. EMBO J 21: 1607-1615.

von Pawel-Rammingen, U., and Bjorck, L. (2003) IdeS and SpeB: immunoglobulin-degrading cysteine proteinases of Streptococcus pyogenes. Curr Opin Microbiol 6: 50-55.

Wang, J.R., and Stinson, M.W. (1994) M protein mediates streptococcal adhesion to HEp-2 cells. Infect Immun 62: 442-448.

Wenig, K., Chatwell, L., von Pawel-Rammingen, U., Bjorck, L., Huber, R., and Sondermann, P. (2004) Structure of the streptococcal endopeptidase IdeS, a cysteine proteinase with strict specificity for IgG. Proc Natl Acad Sci USA 101: 17371-17376.

Whitnack, E., and Beachey, E.H. (1982) Antiopsonic activity of fibrinogen bound to M protein on the surface of Group A streptococci. J Clin Invest 69: 1042-1045.

Whitnack, E., and Beachey, E.H. (1985) Inhibition of complement-mediated opsonization and phagocytosis of Streptococcus pyogenes by D fragments of fibrinogen and fibrin bound to cell surface M protein. J Exp Med 162: 1983-1997.

Wu, M.W. (2007) Characterization of the Variants of Immunoglobulin G degrading Enzyme of Streptococcus pyogenes. M.S. Thesis, Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng-Kung University.

Yan, J.J., Liu, C.C., Ko, W.C., Hsu, S.Y., Wu, H.M., Lin, Y.S., Lin, M.T., Chuang, W.J., and Wu, J.J. (2003) Molecular analysis of Group A streptococcal isolates associated with scarlet fever in southern Taiwan between 1993 and 2002. J Clin Microbiol 41: 4858-4861.

Yang, R., Otten, M.A., Hellmark, T., Collin, M., Bjorck, L., Zhao, M.H., Daha, M.R., and Segelmark, M. (2010) Successful treatment of experimental glomerulonephritis with IdeS and EndoS, IgG-degrading streptococcal enzymes. Nephrol Dial Transplant 25: 2479-2486.