title: A common human TLR1 polymorphism regulates the innate immune response to lipopeptides.
abstract: Toll-like receptors (TLR) are critical mediators of the immune response to pathogens and human polymorphisms in this gene family regulate inflammatory pathways and are associated with susceptibility to infection. Lipopeptides are present in a wide variety of microbes and stimulate immune responses through TLR1/2 or TLR2/6 heterodimers. It is not currently known whether polymorphisms in TLR1 regulate the innate immune response. We stimulated human whole blood with triacylated lipopeptide, a ligand for TLR1/2 heterodimers, and found substantial inter-individual variation in the immune response. We sequenced the coding region of TLR1 and found a non-synonymous polymorphism, I602S (base pair T1805G), that regulated signalling. In comparison to TLR1_602S, the 602I variant mediated substantially greater basal and lipopeptide-induced NF-kappaB signalling in transfected HEK293 cells. These signalling differences among TLR1 variants were also found with stimulation by extracts of Mycobacterium tuberculosis. Furthermore, individuals with the 602II genotype produced substantially more IL-6 than those with the 602SS variant in a lipopeptide-stimulated whole-blood cytokine assay. Together, these observations demonstrate that variation in the inflammatory response to bacterial lipopeptides is regulated by a common TLR1 transmembrane domain polymorphism that could potentially impact the innate immune response and clinical susceptibility to a wide spectrum of pathogens.
authors.affiliation: Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA, and Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. thawn@u.washington.edu
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Hawn
authors.forename: E Ann
authors.initials: EA
authors.lastname: Misch
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Dunstan
authors.forename: Guy E
authors.initials: GE
authors.lastname: Thwaites
authors.forename: Nguyen T N
authors.initials: NT
authors.lastname: Lan
authors.forename: Hoang T
authors.initials: HT
authors.lastname: Quy
authors.forename: Tran T H
authors.initials: TT
authors.lastname: Chau
authors.forename: Stephanie
authors.initials: S
authors.lastname: Rodrigues
authors.forename: Alex
authors.initials: A
authors.lastname: Nachman
authors.forename: Marta
authors.initials: M
authors.lastname: Janer
authors.forename: Tran T
authors.initials: TT
authors.lastname: Hien
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Farrar
authors.forename: Alan
authors.initials: A
authors.lastname: Aderem
mesh_terms: D001426:Bacterial Proteins / Q000276:immunology*; D001483:Base Sequence; D005455:Fluorescent Antibody Technique; D006801:Humans; D007113:Immunity, Innate; D015151:Immunoblotting; D008074:Lipoproteins / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology; D016328:NF-kappa B; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D051194:Toll-Like Receptor 1 / Q000235:genetics*; D014162:Transfection
chemical_list: D001426:Bacterial Proteins; D008074:Lipoproteins; D016328:NF-kappa B; D051194:Toll-Like Receptor 1