title: Domain exchange at the 3' end of the gene encoding the fratricide meningococcal two-partner secretion protein A.
abstract: BACKGROUND
  Two-partner secretion systems in Gram-negative bacteria consist of an outer membrane protein TpsB that mediates the secretion of a cognate TpsA protein into the extracellular milieu. TpsA proteins have diverse, often virulence-related functions, and some of them inhibit the growth of related bacteria. In Neisseria meningitidis, several functions have been attributed to the TpsA proteins. Downstream of the tpsB and tpsA genes, several shorter tpsA-related gene cassettes, called tpsC, are located interspersed with intervening open-reading frames (IORFs). It has been suggested that the tpsC cassettes may recombine with the tpsA gene as a mechanism of antigenic variation. Here, we investigated (i) whether TpsA of N. meningitidis also has growth-inhibitory properties, (ii) whether tpsC cassettes recombine with the tpsA gene, and (iii) what the consequences of such recombination events might be.
  
  
  RESULTS
  We demonstrate that meningococcal TpsA has growth-inhibitory properties and that the IORF located immediately downstream of tpsA confers immunity to the producing strain. Although bioinformatics analysis suggests that recombination between tpsC cassettes and tpsA occurs, detailed analysis of the tpsA gene in a large collection of disease isolates of three clonal complexes revealed that the frequency is very low and cannot be a mechanism of antigenic variation. However, recombination affected growth inhibition. In vitro experiments revealed that recombination can be mediated through acquirement of tpsC cassettes from the environment and it identified the regions involved in the recombination.
  
  
  CONCLUSIONS
  Meningococcal TpsA has growth-inhibitory properties. Recombination between tpsA and tpsC cassettes occurs in vivo but is rare and has consequences for growth inhibition. A recombination model is proposed and we propose that the main goal of recombination is the collection of new IORFs for protection against a variety of TpsA proteins.
authors.affiliation: Department of Molecular Microbiology, Utrecht University, Padualaan 8, Utrecht 3584 CH, The Netherlands. J.A.arenasbusto@uu.nl.
authors.forename: Jesús
authors.initials: J
authors.lastname: Arenas
authors.forename: Kim
authors.initials: K
authors.lastname: Schipper
authors.forename: Peter
authors.initials: P
authors.lastname: van Ulsen
authors.forename: Arie
authors.initials: A
authors.lastname: van der Ende
authors.forename: Jan
authors.initials: J
authors.lastname: Tommassen
mesh_terms: D001425:Bacterial Outer Membrane Proteins / Q000235:genetics*; D058947:Bacterial Secretion Systems / Q000235:genetics*; D004269:DNA, Bacterial / Q000235:genetics; D009345:Neisseria meningitidis / Q000235:genetics* / Q000254:growth & development*; D016366:Open Reading Frames; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA
chemical_list: D001425:Bacterial Outer Membrane Proteins; D058947:Bacterial Secretion Systems; D004269:DNA, Bacterial
references.citation: Nature. 2000 Mar 30;404(6777):502-6
references.pmid: 10761919
references.citation: Mol Microbiol. 2000 Jul;37(1):207-15
references.pmid: 10931317
references.citation: Infect Immun. 1972 Aug;6(2):127-33
references.pmid: 4631911
references.citation: Infect Immun. 2009 Jun;77(6):2285-93
references.pmid: 19289515
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9417-22
references.pmid: 15192148
references.citation: Infect Immun. 2000 Apr;68(4):2082-95
references.pmid: 10722605
references.citation: Infect Immun. 2003 May;71(5):2331-40
references.pmid: 12704102
references.citation: Nature. 2010 Nov 18;468(7322):439-42
references.pmid: 21085179
references.citation: Mol Microbiol. 2001 Apr;40(2):306-13
references.pmid: 11309114
references.citation: BMC Bioinformatics. 2004 Jul 01;5:86
references.pmid: 15230973
references.citation: Mol Microbiol. 1997 Jan;23(1):123-35
references.pmid: 9004226
references.citation: Clin Microbiol Rev. 2004 Jul;17(3):581-611, table of contents
references.pmid: 15258095
references.citation: Proc Natl Acad Sci U S A. 1985 Feb;82(4):1194-8
references.pmid: 3919387
references.citation: FEMS Microbiol Rev. 2009 May;33(3):521-30
references.pmid: 19396954
references.citation: Genomics. 2008 Jan;91(1):78-87
references.pmid: 18031983
references.citation: J Med Microbiol. 1985 Apr;19(2):203-9
references.pmid: 3920399
references.citation: Mol Microbiol. 1993 May;8(4):719-25
references.pmid: 8332064
references.citation: PLoS Genet. 2012;8(8):e1002877
references.pmid: 22912595
references.citation: PLoS Genet. 2007 Feb 16;3(2):e23
references.pmid: 17305430
references.citation: Nature. 1989 Apr 20;338(6217):651-2
references.pmid: 2468090
references.citation: Mol Microbiol. 2003 Nov;50(3):1017-30
references.pmid: 14617158
references.citation: Mol Microbiol. 1999 Mar;31(5):1345-57
references.pmid: 10200956
references.citation: Science. 2005 Aug 19;309(5738):1245-8
references.pmid: 16109881
references.citation: Mol Microbiol. 2008 Oct;70(2):323-40
references.pmid: 18761695
references.citation: Mol Microbiol. 1996 Nov;22(3):509-22
references.pmid: 8939434
references.citation: J Infect Dis. 2005 Apr 15;191(8):1263-71
references.pmid: 15776372
references.citation: Mol Microbiol. 2000 Sep;37(5):1146-58
references.pmid: 10972832
references.citation: Mol Microbiol. 2005 Oct;58(2):510-9
references.pmid: 16194236
references.citation: Genome Biol. 2009;10(10):R110
references.pmid: 19818133
references.citation: FEMS Microbiol Rev. 2006 Mar;30(2):292-319
references.pmid: 16472308
references.citation: J Bacteriol. 2011 May;193(9):2371-2
references.pmid: 21378179
references.citation: Infect Immun. 1992 Aug;60(8):3156-61
references.pmid: 1639486
references.citation: PLoS Genet. 2011 Aug;7(8):e1002217
references.pmid: 21829394
references.citation: Lancet Infect Dis. 2009 Jul;9(7):418-27
references.pmid: 19555901
references.citation: Science. 2000 Mar 10;287(5459):1809-15
references.pmid: 10710307
references.citation: Cell Microbiol. 2008 Dec;10(12):2461-82
references.pmid: 18680551
references.citation: Lancet. 2000 Nov 11;356(9242):1653-4
references.pmid: 11089827
references.citation: Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7986-90
references.pmid: 7644525
references.citation: J Bacteriol. 2010 Jul;192(14):3822-3
references.pmid: 20472803
references.citation: Mol Microbiol. 2003 Oct;50(1):3-13
references.pmid: 14507359
references.citation: FEMS Microbiol Rev. 2005 Apr;29(2):169-83
references.pmid: 15808740
references.citation: Mol Microbiol. 2013 Jan;87(2):254-68
references.pmid: 23163582
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3473-8
references.pmid: 18305155
references.citation: Infect Immun. 2008 Oct;76(10):4649-58
references.pmid: 18678657
references.citation: Vaccine. 2010 Jul 5;28(30):4817-26
references.pmid: 20457291
references.citation: Infect Immun. 1997 Jul;65(7):2613-20
references.pmid: 9199428
references.citation: Infect Immun. 2001 Oct;69(10):6419-26
references.pmid: 11553586
references.citation: Nature. 2000 Sep 7;407(6800):98-102
references.pmid: 10993081
references.citation: Genetics. 2004 Jan;166(1):25-32
references.pmid: 15020403
references.citation: J Infect Dis. 1993 Jun;167(6):1320-9
references.pmid: 8501321
references.citation: J Bacteriol. 2007 Nov;189(22):7968-76
references.pmid: 17873034
references.citation: Biochim Biophys Acta. 2004 Nov 11;1694(1-3):235-57
references.pmid: 15546669
references.citation: Nature. 1988 Nov 24;336(6197):392-5
references.pmid: 2904127