title: Single nucleotide polymorphisms in toll-like receptor 6 are associated with altered lipopeptide- and mycobacteria-induced interleukin-6 secretion.
abstract: Toll-like receptors (TLRs) are critical mediators of the immune response to pathogens. The influence of human TLR6 polymorphisms on susceptibility to infection is only partially understood. Most microbes contain lipopeptides recognized by TLR2/1 or TLR2/6 heterodimers. Our aim was to determine whether single nucleotide polymorphisms in TLR6 are associated with altered immune responses to lipopeptides and whole mycobacteria. We sequenced the TLR6 coding region in 100 healthy South African adults to assess genetic variation and determined associations between polymorphisms and lipopeptide- and mycobacteria-induced interleukin (IL)-6 production in whole blood. We found two polymorphisms, C745T and G1083C, that were associated with altered IL-6 secretion. G1083C was associated with altered IL-6 levels in response to lipopeptides, Mycobacterium tuberculosis lysate (Mtb lysate, P=0.018) and Bacille Calmette-Guerin (BCG P=0.039). The 745T allele was also associated with lower NF-κB signaling in response to di-acylated lipopeptide, PAM2 (P=0.019) or Mtb (P=0.026) in an HEK293 cell line reconstitution assay, compared with the 745C allele. We conclude that TLR6 polymorphisms may be associated with altered lipopeptide-induced cytokine responses and recognition of Mtb. These studies provide new insight into the role of TLR6 variation and the innate immune response to human infection.
authors.affiliation: South African Tuberculosis Vaccine Initiative, University of Cape Town, South Africa.
authors.forename: M S
authors.initials: MS
authors.lastname: Shey
authors.forename: A K
authors.initials: AK
authors.lastname: Randhawa
authors.forename: M
authors.initials: M
authors.lastname: Bowmaker
authors.forename: E
authors.initials: E
authors.lastname: Smith
authors.forename: T J
authors.initials: TJ
authors.lastname: Scriba
authors.forename: M
authors.initials: M
authors.lastname: de Kock
authors.forename: H
authors.initials: H
authors.lastname: Mahomed
authors.forename: G
authors.initials: G
authors.lastname: Hussey
authors.forename: T R
authors.initials: TR
authors.lastname: Hawn
authors.forename: W A
authors.initials: WA
authors.lastname: Hanekom
mesh_terms: D000328:Adult; D016207:Cytokines / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007155:Immunologic Factors / Q000235:genetics; D015850:Interleukin-6 / Q000378:metabolism*; D055666:Lipopeptides / Q000378:metabolism; D009161:Mycobacterium; D009163:Mycobacterium bovis / Q000235:genetics / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051216:Toll-Like Receptor 6 / Q000235:genetics*; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D016207:Cytokines; D007155:Immunologic Factors; D015850:Interleukin-6; D055666:Lipopeptides; D016328:NF-kappa B; D051216:Toll-Like Receptor 6; D051193:Toll-Like Receptors
references.citation: Ann N Y Acad Sci. 2005 Dec;1062:95-103
references.pmid: 16461792
references.citation: BMC Immunol. 2008 Aug 08;9:46
references.pmid: 18691413
references.citation: Eur J Immunogenet. 1998 Apr-Jun;25(2-3):267
references.pmid: 9615916
references.citation: Infect Immun. 2004 Mar;72(3):1657-65
references.pmid: 14977973
references.citation: Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14459-63
references.pmid: 10588727
references.citation: J Exp Med. 2005 Dec 19;202(12):1715-24
references.pmid: 16365150
references.citation: J Immunol. 2001 Jul 15;167(2):987-94
references.pmid: 11441107
references.citation: Infect Immun. 2000 Nov;68(11):6398-401
references.pmid: 11035751
references.citation: Science. 1998 Dec 11;282(5396):2085-8
references.pmid: 9851930
references.citation: Immunol Rev. 2009 Jan;227(1):221-33
references.pmid: 19120487
references.citation: Immunology. 2000 Sep;101(1):1-10
references.pmid: 11012747
references.citation: J Mol Med (Berl). 2003 Jun;81(6):368-72
references.pmid: 12743710
references.citation: Int Immunopharmacol. 2004 Oct;4(10-11):1287-300
references.pmid: 15313427
references.citation: J Immunol. 2005 Aug 15;175(4):2534-40
references.pmid: 16081826
references.citation: Eur J Immunol. 2002 Dec;32(12):3337-47
references.pmid: 12432564
references.citation: Mol Cell Proteomics. 2002 Apr;1(4):304-13
references.pmid: 12096112
references.citation: Annu Rev Genomics Hum Genet. 2001;2:373-400
references.pmid: 11701655
references.citation: Microbiology (Reading). 2007 Mar;153(Pt 3):652-658
references.pmid: 17322184
references.citation: Clin Sci (Lond). 2008 Mar;114(5):347-60
references.pmid: 18230059
references.citation: Trends Immunol. 2006 Jan;27(1):49-55
references.pmid: 16310411
references.citation: Genes Immun. 2004 Aug;5(5):343-6
references.pmid: 15266299
references.citation: J Biol Chem. 2006 Apr 7;281(14):9049-57
references.pmid: 16455646
references.citation: Methods Mol Biol. 2003;212:241-62
references.pmid: 12491915
references.citation: Int Immunol. 2001 Jul;13(7):933-40
references.pmid: 11431423
references.citation: Genome Res. 1998 Mar;8(3):195-202
references.pmid: 9521923
references.citation: BMC Med Genet. 2005 Sep 28;6:34
references.pmid: 16188043
references.citation: J Immunol. 2003 Apr 1;170(7):3451-4
references.pmid: 12646604
references.citation: J Biol Chem. 2005 Nov 4;280(44):36616-25
references.pmid: 16129684
references.citation: Genome Biol. 2003;4(9):117
references.pmid: 12952525
references.citation: PLoS Genet. 2009 Jul;5(7):e1000562
references.pmid: 19609346
references.citation: Annu Rev Genet. 2006;40:469-86
references.pmid: 17094741
references.citation: Tissue Antigens. 2006 Feb;67(2):97-110
references.pmid: 16441480
references.citation: Immunol Rev. 2009 Jan;227(1):248-63
references.pmid: 19120489
references.citation: Cell. 2006 Feb 24;124(4):783-801
references.pmid: 16497588
references.citation: J Immunol. 2007 Jun 15;178(12):7520-4
references.pmid: 17548585
references.citation: J Immunol. 2002 Jul 1;169(1):10-4
references.pmid: 12077222
references.citation: Curr Protoc Bioinformatics. 2003 Aug;Chapter 11:Unit11.2
references.pmid: 18428695
references.citation: J Immunol. 2006 Jul 1;177(1):422-9
references.pmid: 16785538
references.citation: J Immunol. 2008 May 1;180(9):6149-58
references.pmid: 18424736
references.citation: Eur J Immunol. 2007 Aug;37(8):2280-9
references.pmid: 17595679
references.citation: PLoS One. 2007 Dec 19;2(12):e1318
references.pmid: 18091991
references.citation: J Immunol. 1999 Oct 1;163(7):3920-7
references.pmid: 10490993
references.citation: Vaccine. 2008 Mar 25;26(14):1731-6
references.pmid: 18325643
references.citation: Lancet Infect Dis. 2005 Mar;5(3):156-64
references.pmid: 15766650
references.citation: J Clin Invest. 1998 Oct 1;102(7):1369-76
references.pmid: 9769329
references.citation: Am J Respir Crit Care Med. 2008 Oct 1;178(7):710-20
references.pmid: 18635889