title: Protective immunogenicity of group A streptococcal M-related proteins.
abstract: Many previous studies have focused on the surface M proteins of group A streptococci (GAS) as virulence determinants and protective antigens. However, the majority of GAS isolates express M-related protein (Mrp) in addition to M protein, and both have been shown to be required for optimal virulence. In the current study, we evaluated the protective immunogenicity of Mrp to determine its potential as a vaccine component that may broaden the coverage of M protein-based vaccines. Sequence analyses of 33 mrp genes indicated that there are three families of structurally related Mrps (MrpI, MrpII, and MrpIII). N-terminal peptides of Mrps were cloned, expressed, and purified from M type 2 (M2) (MrpI), M4 (MrpII), and M49 (MrpIII) GAS. Rabbit antisera against the Mrps reacted at high titers with the homologous Mrp, as determined by enzyme-linked immunosorbent assay, and promoted bactericidal activity against GAS emm types expressing Mrps within the same family. Mice passively immunized with rabbit antisera against MrpII were protected against challenge infections with M28 GAS. Assays for Mrp antibodies in serum samples from 281 pediatric subjects aged 2 to 16 indicated that the Mrp immune response correlated with increasing age of the subjects. Affinity-purified human Mrp antibodies promoted bactericidal activity against a number of GAS representing different emm types that expressed an Mrp within the same family but showed no activity against emm types expressing an Mrp from a different family. Our results indicate that Mrps have semiconserved N-terminal sequences that contain bactericidal epitopes which are immunogenic in humans. These findings may have direct implications for the development of GAS vaccines.
authors: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA Department of Microbiology, Immunology and Biochemistry, Memphis, Tennessee, USA Department of Veterans Affairs Medical Center, Memphis, Tennessee, USA jbdale@uthsc.edu.
authors: James B
authors: JB
authors: Dale
authors: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA Department of Veterans Affairs Medical Center, Memphis, Tennessee, USA.
authors: Shannon E
authors: SE
authors: Niedermeyer
authors: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA Department of Veterans Affairs Medical Center, Memphis, Tennessee, USA.
authors: Tina
authors: T
authors: Agbaosi
authors: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA Department of Veterans Affairs Medical Center, Memphis, Tennessee, USA St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Nicholas D
authors: ND
authors: Hysmith
authors: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA Department of Veterans Affairs Medical Center, Memphis, Tennessee, USA.
authors: Thomas A
authors: TA
authors: Penfound
authors: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA Department of Veterans Affairs Medical Center, Memphis, Tennessee, USA.
authors: Claudia M
authors: CM
authors: Hohn
authors: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA Department of Veterans Affairs Medical Center, Memphis, Tennessee, USA.
authors: Matthew
authors: M
authors: Pullen
authors: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA Department of Veterans Affairs Medical Center, Memphis, Tennessee, USA.
authors: Michael I
authors: MI
authors: Bright
authors: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA Department of Veterans Affairs Medical Center, Memphis, Tennessee, USA.
authors: Daniel S
authors: DS
authors: Murrell
authors: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA Department of Veterans Affairs Medical Center, Memphis, Tennessee, USA.
authors: Lori E
authors: LE
authors: Shenep
authors: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA Department of Veterans Affairs Medical Center, Memphis, Tennessee, USA.
authors: Harry S
authors: HS
authors: Courtney
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000595:Amino Acid Sequence; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology*; D000942:Antigens, Bacterial / Q000276:immunology*; D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007106:Immune Sera / Q000276:immunology; D007116:Immunization, Passive; D008297:Male; D051379:Mice; D010802:Phylogeny; D011817:Rabbits; D011994:Recombinant Proteins; D016415:Sequence Alignment; D013290:Streptococcal Infections / Q000276:immunology; D013297:Streptococcus pyogenes / Q000737:chemistry* / Q000276:immunology*
chemical_list: D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D007106:Immune Sera; D011994:Recombinant Proteins
references: Vaccine. 2010 Jul 12;28(31):5017-22
references: 20546830
references: East Afr Med J. 1996 Apr;73(4):215-7
references: 8706601
references: Microbes Infect. 2011 Apr;13(4):413-8
references: 21241819
references: J Infect Dis. 2004 Jan 1;189(1):79-89
references: 14702157
references: J Exp Med. 1986 May 1;163(5):1191-202
references: 2422314
references: Proc Natl Acad Sci U S A. 1989 Jun;86(12):4741-5
references: 2660147
references: Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8661-5
references: 1528877
references: Med Microbiol Immunol. 1994 Feb;183(1):33-42
references: 8202029
references: Infect Immun. 1995 Jan;63(1):9-20
references: 7806389
references: Am J Med Sci. 1996 Jan;311(1):41-54
references: 8571986
references: J Infect Dis. 1996 Apr;173(4):896-900
references: 8603968
references: Mol Microbiol. 1996 Feb;19(3):429-41
references: 8830235
references: Infect Immun. 1996 Jun;64(6):2193-200
references: 8675326
references: Med Microbiol Immunol. 1996 May;185(1):39-47
references: 8803952
references: Vaccine. 1999 Jan;17(2):193-200
references: 9987154
references: J Infect Dis. 2005 Sep 1;192(5):760-70
references: 16088825
references: Clin Infect Dis. 2005 Oct 15;41(8):1114-22
references: 16163629
references: Lancet Infect Dis. 2005 Nov;5(11):685-94
references: 16253886
references: Mol Microbiol. 2006 Feb;59(3):936-47
references: 16420362
references: Nat Biotechnol. 2006 Feb;24(2):191-7
references: 16415855
references: J Bacteriol. 2007 Mar;189(5):1514-22
references: 17142387
references: N Engl J Med. 2007 Aug 2;357(5):470-6
references: 17671255
references: Clin Infect Dis. 2007 Oct 1;45(7):853-62
references: 17806049
references: J Clin Microbiol. 2009 Apr;47(4):1155-65
references: 19158266
references: Clin Infect Dis. 2009 Jul 1;49(1):78-84
references: 19480575
references: Lancet Infect Dis. 2009 Oct;9(10):611-6
references: 19778763
references: Am J Cardiol. 2010 Jun 15;105(12):1809-14
references: 20538135
references: Vaccine. 2011 Oct 26;29(46):8175-8
references: 21920403
references: Circulation. 2012 Jun 26;125(25):3127-32
references: 22626741
references: Vaccine. 2013 Mar 15;31(12):1576-81
references: 23375817
references: PLoS One. 2013;8(10):e78719
references: 24205299
references: Pediatr Infect Dis J. 2014 Feb;33(2):208-10
references: 23934204
references: Clin Vaccine Immunol. 2014 Oct;21(10):1421-5
references: 25080552
references: Infect Immun. 2010 Sep;78(9):4051-67
references: 20624906