title: Computational analyses of an evolutionary arms race between mammalian immunity mediated by immunoglobulin A and its subversion by bacterial pathogens.
abstract: IgA is the predominant immunoglobulin isotype in mucosal tissues and external secretions, playing important roles both in defense against pathogens and in maintenance of commensal microbiota. Considering the complexity of its interactions with the surrounding environment, IgA is a likely target for diversifying or positive selection. To investigate this possibility, the action of natural selection on IgA was examined in depth with six different methods: CODEML from the PAML package and the SLAC, FEL, REL, MEME and FUBAR methods implemented in the Datamonkey webserver. In considering just primate IgA, these analyses show that diversifying selection targeted five positions of the Cα1 and Cα2 domains of IgA. Extending the analysis to include other mammals identified 18 positively selected sites: ten in Cα1, five in Cα2 and three in Cα3. All but one of these positions display variation in polarity and charge. Their structural locations suggest they indirectly influence the conformation of sites on IgA that are critical for interaction with host IgA receptors and also with proteins produced by mucosal pathogens that prevent their elimination by IgA-mediated effector mechanisms. Demonstrating the plasticity of IgA in the evolution of different groups of mammals, only two of the eighteen selected positions in all mammals are included in the five selected positions in primates. That IgA residues subject to positive selection impact sites targeted both by host receptors and subversive pathogen ligands highlights the evolutionary arms race playing out between mammals and pathogens, and further emphasizes the importance of IgA in protection against mucosal pathogens.
authors.affiliation: CIBIO Centro de Investigação em Biodiversidade e Recursos Genéticos/InBio Laboratório Associado, Universidade do Porto, Vairão, Portugal ; Departamento de Biologia, Faculdade de Ciências, Universidade do Porto, Porto, Portugal ; SaBio - Instituto de Investigación en Recursos Cinegéticos (CSIC-UCLM-JCCM), Ciudad Real, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Pinheiro
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Woof
authors.forename: Laurent
authors.initials: L
authors.lastname: Abi-Rached
authors.forename: Peter
authors.initials: P
authors.lastname: Parham
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Esteves
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001419:Bacteria / Q000472:pathogenicity*; D005075:Biological Evolution; D003062:Codon; D019295:Computational Biology; D007070:Immunoglobulin A / Q000737:chemistry / Q000502:physiology*; D008322:Mammals / Q000276:immunology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D012641:Selection, Genetic
chemical_list: D003062:Codon; D007070:Immunoglobulin A
references.citation: Bioinformatics. 2005 May 15;21(10):2531-3
references.pmid: 15713735
references.citation: Genetics. 1998 Mar;148(3):929-36
references.pmid: 9539414
references.citation: Dev Comp Immunol. 2005;29(3):185-203
references.pmid: 15572068
references.citation: Annu Rev Immunol. 2003;21:177-204
references.pmid: 12524384
references.citation: Genetics. 2003 Jul;164(3):1229-36
references.pmid: 12871927
references.citation: Mol Biol Evol. 2007 Aug;24(8):1586-91
references.pmid: 17483113
references.citation: Mol Biol Evol. 2006 Oct;23(10):1891-901
references.pmid: 16818476
references.citation: Bioinformatics. 2006 Oct 15;22(20):2493-9
references.pmid: 16895925
references.citation: Mol Biol Evol. 2010 Sep;27(9):2172-86
references.pmid: 20410160
references.citation: J Biol Chem. 2001 Mar 16;276(11):8197-204
references.pmid: 11096107
references.citation: Int J Immunogenet. 2006 Jun;33(3):171-7
references.pmid: 16712647
references.citation: J Pathol. 2006 Jan;208(2):270-82
references.pmid: 16362985
references.citation: J Immunol. 2006 Sep 15;177(6):3913-9
references.pmid: 16951354
references.citation: Trends Biochem Sci. 2000 Jun;25(6):300-2
references.pmid: 10838572
references.citation: MAbs. 2010 May-Jun;2(3):212-20
references.pmid: 20400859
references.citation: J Biol Chem. 2006 Jan 20;281(3):1389-93
references.pmid: 16293625
references.citation: Infect Immun. 2005 Mar;73(3):1515-22
references.pmid: 15731049
references.citation: J Mol Biol. 1999 Mar 12;286(5):1421-47
references.pmid: 10064707
references.citation: Mol Biol Evol. 2011 Oct;28(10):2731-9
references.pmid: 21546353
references.citation: J Allergy Clin Immunol. 2010 Feb;125(2 Suppl 2):S41-52
references.pmid: 20176268
references.citation: J Biol Chem. 2011 Sep 23;286(38):33118-24
references.pmid: 21784854
references.citation: Annu Rev Immunol. 2007;25:21-50
references.pmid: 17029568
references.citation: Mol Biol Evol. 2005 Apr;22(4):1107-18
references.pmid: 15689528
references.citation: J Immunol. 2005 Nov 15;175(10):6694-701
references.pmid: 16272325
references.citation: Nature. 2003 Jun 5;423(6940):614-20
references.pmid: 12768205
references.citation: Mucosal Immunol. 2011 Nov;4(6):590-7
references.pmid: 21937984
references.citation: Eur J Immunogenet. 2002 Dec;29(6):529-35
references.pmid: 12437613
references.citation: J Immunol. 1994 Jun 1;152(11):5299-304
references.pmid: 8189047
references.citation: EMBO J. 1989 Dec 20;8(13):4041-7
references.pmid: 2512120
references.citation: Comput Appl Biosci. 1997 Oct;13(5):555-6
references.pmid: 9367129
references.citation: Infect Immun. 2003 Mar;71(3):1462-9
references.pmid: 12595464
references.citation: J Immunol. 2007 Jun 15;178(12):7943-54
references.pmid: 17548632
references.citation: PLoS Genet. 2012;8(7):e1002764
references.pmid: 22807683
references.citation: PLoS Genet. 2008 Aug 01;4(8):e1000144
references.pmid: 18670650
references.citation: Infect Immun. 2003 May;71(5):2563-70
references.pmid: 12704129
references.citation: J Biol Chem. 1999 Aug 13;274(33):23508-14
references.pmid: 10438530
references.citation: Front Immunol. 2012 May 03;3:100
references.pmid: 22563329
references.citation: Genet Res. 2003 Apr;81(2):115-21
references.pmid: 12872913
references.citation: Eur J Immunol. 2009 Apr;39(4):1147-56
references.pmid: 19266484
references.citation: J Immunol. 1993 Jun 15;150(12):5457-65
references.pmid: 8515070
references.citation: Nucleic Acids Res. 1994 Nov 11;22(22):4673-80
references.pmid: 7984417
references.citation: Mol Biol Evol. 2000 Oct;17(10):1446-55
references.pmid: 11018152
references.citation: Hum Mol Genet. 2004 Oct 1;13 Spec No 2:R245-54
references.pmid: 15358731
references.citation: Proc Natl Acad Sci U S A. 2007 Sep 18;104(38):15051-6
references.pmid: 17848512
references.citation: Nucleic Acids Res. 2004 Mar 19;32(5):1792-7
references.pmid: 15034147
references.citation: J Mol Biol. 2009 Jun 12;389(3):559-74
references.pmid: 19393662
references.citation: J Biol Chem. 1992 Apr 15;267(11):7359-67
references.pmid: 1559979
references.citation: Mucosal Immunol. 2011 Nov;4(6):603-11
references.pmid: 21975936