title: Natural variation in the promoter of the gene encoding the Mga regulator alters host-pathogen interactions in group a Streptococcus carrier strains.
abstract: Humans commonly carry pathogenic bacteria asymptomatically, but the molecular factors underlying microbial asymptomatic carriage are poorly understood. We previously reported that two epidemiologically unassociated serotype M3 group A Streptococcus (GAS) carrier strains had an identical 12-bp deletion in the promoter of the gene encoding Mga, a global positive gene regulator. Herein, we report on studies designed to test the hypothesis that the identified 12-bp deletion in the mga promoter alters GAS virulence, thereby potentially contributing to the asymptomatic carrier phenotype. Using allelic exchange, we introduced the variant promoter into a serotype M3 invasive strain and the wild-type promoter into an asymptomatic carrier strain. Compared to strains with the wild-type mga promoter, we discovered that strains containing the promoter with the 12-bp deletion produced significantly fewer mga and Mga-regulated gene transcripts. Consistent with decreased mga transcripts, strains containing the variant mga promoter were also significantly less virulent in in vivo and ex vivo models of GAS disease. Further, we provide evidence that the pleiotropic regulator protein CodY binds to the mga promoter and that the 12-bp deletion in the mga promoter reduces CodY-mediated mga transcription. We conclude that the naturally occurring 12-bp deletion in the mga promoter significantly alters the pathogen-host interaction of these asymptomatic carrier strains. Our findings provide new insight into the molecular basis of the carrier state of an important human pathogen.
authors: Section of Infectious Diseases, Department of Pediatrics, Texas Children's Hospital and Baylor College of MedicineHouston, Texas, USA.
authors: Anthony R
authors: AR
authors: Flores
authors: Randall J
authors: RJ
authors: Olsen
authors: Andrea
authors: A
authors: Wunsche
authors: Muthiah
authors: M
authors: Kumaraswami
authors: Samuel A
authors: SA
authors: Shelburne
authors: Ronan K
authors: RK
authors: Carroll
authors: James M
authors: JM
authors: Musser
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D002353:Carrier State / Q000382:microbiology*; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005816:Genetic Complementation Test; D014644:Genetic Variation; D054884:Host-Pathogen Interactions; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011995:Recombination, Genetic; D017384:Sequence Deletion; D013290:Streptococcal Infections / Q000382:microbiology*; D013297:Streptococcus pyogenes / Q000235:genetics / Q000472:pathogenicity*; D014158:Transcription, Genetic; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D037521:Virulence Factors; C068267:mry protein, Streptococcus pyogenes
references: Mol Microbiol. 1993 Mar;7(6):893-903
references: 8483419
references: Proc Natl Acad Sci U S A. 2006 May 30;103(22):8487-92
references: 16687478
references: mBio. 2012 Nov 06;3(6):e00413-12
references: 23131832
references: J Immunol. 1962 Sep;89:307-13
references: 14461914
references: Pediatrics. 2004 Nov;114(5):1212-9
references: 15520098
references: J Bacteriol. 1999 Sep;181(17):5373-83
references: 10464209
references: Proc Natl Acad Sci U S A. 2006 May 2;103(18):7059-64
references: 16636287
references: Clin Infect Dis. 2010 Feb 15;50(4):481-90
references: 20067422
references: FEMS Immunol Med Microbiol. 2011 Jul;62(2):123-39
references: 21539625
references: J Clin Invest. 1962 Mar;41:568-74
references: 14459435
references: Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4371-6
references: 20142485
references: J Med Microbiol. 2007 Jun;56(Pt 6):707-714
references: 17510253
references: J Exp Med. 1948 Jun 1;87(6):521-33
references: 18858642
references: Clin Infect Dis. 2005 Feb 15;40(4):511-8
references: 15712072
references: Clin Infect Dis. 2008 Oct 15;47(8):989-96
references: 18781875
references: J Clin Invest. 2011 May;121(5):1956-68
references: 21490401
references: Infect Immun. 1996 Feb;64(2):503-10
references: 8550199
references: Proc Natl Acad Sci U S A. 1985 Dec;82(23):8144-8
references: 3906656
references: Cell Microbiol. 2000 Aug;2(4):283-92
references: 11207585
references: Infect Immun. 2000 Dec;68(12):6542-53
references: 11083763
references: Pediatrics. 2003 Jul;112(1 Pt 1):e61-5
references: 12837907
references: Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11833-8
references: 15282372
references: J Infect Dis. 2003 Sep 15;188(6):818-27
references: 12964112
references: Arch Dis Child. 1994 Oct;71(4):318-22
references: 7979524
references: Nat Genet. 2011 Nov 13;43(12):1275-80
references: 22081229
references: Int J Med Microbiol. 2006 Aug;296(4-5):259-75
references: 16531115
references: PLoS Pathog. 2008 Sep 05;4(9):e1000145
references: 18773116
references: JAMA. 1997 Jan 1;277(1):38-43
references: 8980208
references: Microb Pathog. 1995 Mar;18(3):153-66
references: 7565010
references: J Bacteriol. 2011 Aug;193(16):4153-65
references: 21705595
references: Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3800-4
references: 15728391
references: Infect Immun. 2000 Feb;68(2):535-42
references: 10639414
references: Pediatrics. 2010 Sep;126(3):e557-64
references: 20696723
references: Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2668-72
references: 1672766
references: J Med Microbiol. 2004 Sep;53(Pt 9):821-832
references: 15314188
references: J Infect Dis. 2002 Apr 1;185(7):915-20
references: 11920315
references: FEMS Microbiol Rev. 2007 Jan;31(1):52-63
references: 17233635
references: J Exp Med. 1957 Oct 1;106(4):525-44
references: 13475611
references: Proc Natl Acad Sci U S A. 2005 Jun 21;102(25):9014-9
references: 15956184
references: Annu Rev Genet. 2006;40:307-33
references: 17094739
references: Infect Immun. 1999 Dec;67(12):6487-95
references: 10569767
references: N Engl J Med. 2003 May 1;348(18):1747-55
references: 12724480
references: Proc Natl Acad Sci U S A. 1987 Dec;84(23):8677-81
references: 2446327
references: Lancet. 2004 Jun 5;363(9424):1871-2
references: 15183627
references: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3473-8
references: 18305155
references: Mol Microbiol. 2006 Oct;62(2):491-508
references: 16965517
references: Ann Intern Med. 2006 Mar 7;144(5):318-25
references: 16520472
references: Infect Immun. 2001 Feb;69(2):822-31
references: 11159974
references: Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):888-93
references: 20080771
references: J Bacteriol. 1995 Nov;177(22):6619-24
references: 7592441
references: BMC Genomics. 2008 Sep 22;9:433
references: 18808706
references: Eur J Clin Microbiol Infect Dis. 2009 Sep;28(9):1159-65
references: 19434432
references: J Bacteriol. 1997 Aug;179(16):5178-87
references: 9260962
references: J Exp Med. 1959 Aug 1;110(2):271-92
references: 13673139
references: Proc Natl Acad Sci U S A. 2002 Jul 23;99(15):10078-83
references: 12122206
references: JAMA. 2006 Apr 12;295(14):1668-74
references: 16609088
references: Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13251-6
references: 9371832
references: Proc Natl Acad Sci U S A. 2011 May 3;108(18):7481-6
references: 21518885
references: J Clin Invest. 1962 Mar;41:575-8
references: 14459436
references: Mol Microbiol. 2007 Jun;64(5):1319-31
references: 17542923