title: Application of the C3-binding motif of streptococcal pyrogenic exotoxin B to protect mice from invasive group a streptococcal infection.
abstract: Group A streptococcus (GAS) is an important human pathogen that produces several extracellular exotoxins to facilitate invasion and infection. Streptococcal pyrogenic exotoxin B (SPE B) has been demonstrated to be an important virulence factor of GAS. Our previous studies indicate that SPE B cleaves complement 3 (C3) and inhibits the activation of complement pathways. In this study, we constructed and expressed recombinant fragments of SPE B to examine the C3-binding site of SPE B. Using enzyme-linked immunosorbent assays and pull-down assays, we found that the C-terminal domain, containing amino-acid residues 345-398, of SPE B was the major binding site of human serum C3. We further identified a major, Ala376-Pro398, and a minor C3-binding motif, Gly346-Gly360, that both mediated the binding of C3 complement. Immunization with the C3-binding motifs protected mice against challenge with a lethal dose of non-invasive M49 strain GAS but not invasive M1 strains. To achieve higher efficiency against invasive M1 GAS infection, a combination of synthetic peptides derived from C-terminal epitope of streptolysin S (SLSpp) and from the major C3-binding motif of SPE B (PP6, Ala376-Pro398) was used to elicit specific immune response to those two important streptococcal exotoxins. Death rates and the severity of skin lesions decreased significantly in PP6/SLSpp-immunized mice that were infected with invasive M1 strains of GAS. These results indicate a combination of the C3-binding motif of SPE B and the protective epitope of SLS could be used as a subunit vaccine against invasive M1 strains group A streptococcal infection.
authors: Department of Nursing, I-Shou University, Kaohsiung City, Taiwan.
authors: Chih-Feng
authors: CF
authors: Kuo
authors: Department of Biological Science and Technology, I-Shou University, Kaohsiung City, Taiwan.
authors: Nina
authors: N
authors: Tsao
authors: Department of Biological Science and Technology, I-Shou University, Kaohsiung City, Taiwan.
authors: Miao-Hui
authors: MH
authors: Cheng
authors: Department of Biological Science and Technology, I-Shou University, Kaohsiung City, Taiwan.
authors: Hsiu-Chen
authors: HC
authors: Yang
authors: Department of Biological Science and Technology, I-Shou University, Kaohsiung City, Taiwan.
authors: Yu-Chieh
authors: YC
authors: Wang
authors: Department of Biological Science and Technology, I-Shou University, Kaohsiung City, Taiwan.
authors: Ying-Pin
authors: YP
authors: Chen
authors: Department of Pathology, E-DA Hospital, Kaohsiung City, Taiwan.
authors: Kai-Jen
authors: KJ
authors: Lin
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000276:immunology*; D003176:Complement C3 / Q000276:immunology*; D000939:Epitopes; D005098:Exotoxins / Q000276:immunology*; D051379:Mice; D013290:Streptococcal Infections / Q000276:immunology* / Q000517:prevention & control*; D022541:Streptococcal Vaccines / Q000276:immunology*; D013297:Streptococcus pyogenes / Q000276:immunology
chemical_list: D001426:Bacterial Proteins; D003176:Complement C3; D000939:Epitopes; D005098:Exotoxins; D022541:Streptococcal Vaccines; C027951:erythrogenic toxin
references: Infect Immun. 2008 Mar;76(3):1163-9
references: 18174338
references: J Biol Chem. 2008 Mar 7;283(10):6253-60
references: 18160402
references: J Biol Chem. 2008 Jun 20;283(25):17579-93
references: 18434316
references: J Biol Chem. 2008 Aug 8;283(32):22113-20
references: 18550524
references: J Immunol. 2008 Dec 1;181(11):7463-7
references: 19017934
references: J Clin Microbiol. 2009 Apr;47(4):1155-65
references: 19158266
references: J Mol Biol. 2009 Oct 30;393(3):693-703
references: 19712682
references: Curr Opin Infect Dis. 2009 Dec;22(6):544-52
references: 19797947
references: Lab Invest. 2010 Oct;90(10):1492-506
references: 20458278
references: Trop Med Int Health. 2011 Jan;16(1):2-11
references: 21371205
references: Nat Rev Microbiol. 2011 Oct;9(10):724-36
references: 21921933
references: Biol Chem. 2011 Dec;392(12):1077-88
references: 22050223
references: J Immunol. 2012 Jan 1;188(1):426-35
references: 22140259
references: Discov Med. 2012 May;13(72):329-42
references: 22642914
references: Drugs. 2012 Jun 18;72(9):1213-27
references: 22686614
references: Med Microbiol Immunol. 2012 Aug;201(3):357-69
references: 22610375
references: J Biol Chem. 2012 Jul 13;287(29):24412-26
references: 22645124
references: PLoS One. 2013;8(1):e55028
references: 23383045
references: J Biol Chem. 2013 May 10;288(19):13317-24
references: 23532847
references: J Biol Chem. 2013 May 31;288(22):15854-64
references: 23589297
references: J Biol Chem. 2013 Nov 8;288(45):32172-83
references: 24064215
references: Mol Microbiol. 2000 Oct;38(2):242-53
references: 11069651
references: Proc Natl Acad Sci U S A. 2000 Feb 29;97(5):2235-40
references: 10681429
references: PLoS One. 2013;8(11):e81298
references: 24278414
references: Immunology. 2001 Jul;103(3):390-8
references: 11454069
references: Infect Immun. 2001 Nov;69(11):7187-9
references: 11598100
references: Infect Immun. 2002 Apr;70(4):2166-70
references: 11895983
references: Infect Immun. 2003 Jan;71(1):211-7
references: 12496168
references: J Biol Chem. 2003 May 9;278(19):17336-43
references: 12621045
references: Microb Pathog. 2004 May;36(5):273-85
references: 15043862
references: Microb Pathog. 1993 Nov;15(5):327-46
references: 7516997
references: Infect Immun. 1996 Feb;64(2):503-10
references: 8550199
references: Infect Immun. 1996 Nov;64(11):4744-50
references: 8890235
references: Kidney Int. 1998 Aug;54(2):509-17
references: 9690217
references: Kidney Int. 1998 Sep;54(3):819-26
references: 9734606
references: Mol Microbiol. 2005 Apr;56(1):28-39
references: 15773976
references: Kidney Int. 2005 Sep;68(3):1120-9
references: 16105042
references: Clin Infect Dis. 2005 Oct 15;41(8):1114-22
references: 16163629
references: Biochem Biophys Res Commun. 2006 Jan 20;339(3):779-84
references: 16329996
references: Nat Immunol. 2007 Apr;8(4):430-7
references: 17351618
references: Kidney Int. 2007 Sep;72(6):716-24
references: 17637712
references: J Biol Chem. 2007 Oct 12;282(41):30051-61
references: 17699522