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Single nucleotide polymorphisms in toll-like receptor 6 are associated with altered lipopeptide- and mycobacteria-induced interleukin-6 secretion

Genes & Immunity volume 11, pages 561–572 (2010)Cite this article

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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.

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Acknowledgements

We thank the adult volunteers who participated in the study and also the immunology team at the SATVI research site in Worcester for obtaining informed consent and collecting blood from the participants. We also thank the National Bioinformatics Node (NBN) at the University of Cape Town for providing the PhredPhrap/Consed software. We also thank Rick Wells for excellent technical assistance and Marta Janer and Sarah Li for genotyping work. This work was supported by the Dana Foundation (TRH and WAH), NIH NO1-AI-70022 (TRH and WAH) and the Burroughs Wellcome Foundation (TRH).

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  1. T R Hawn and W A Hanekom: These authors contributed equally to this work.

Authors and Affiliations

  1. South African Tuberculosis Vaccine Initiative, School of Child and Adolescent Health and Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa

    M S Shey, M Bowmaker, E Smith, T J Scriba, M de Kock, H Mahomed, G Hussey & W A Hanekom

  2. Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA

    A K Randhawa & T R Hawn

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  1. M S Shey
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Correspondence to W A Hanekom.

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Shey, M., Randhawa, A., Bowmaker, M. et al. Single nucleotide polymorphisms in toll-like receptor 6 are associated with altered lipopeptide- and mycobacteria-induced interleukin-6 secretion. Genes Immun 11, 561–572 (2010). https://doi.org/10.1038/gene.2010.14

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