Human genetic diversity regulating the TLR10/TLR1/TLR6 locus confers increased cytokines in response to Chlamydia trachomatis.

Journal Article (Journal Article)

Human genetic diversity can have profound effects on health outcomes upon exposure to infectious agents. For infections with Chlamydia trachomatis (C. trachomatis), the wide range of genital and ocular disease manifestations are likely influenced by human genetic differences that regulate interactions between C. trachomatis and host cells. We leveraged this diversity in cellular responses to demonstrate the importance of variation at the Toll-like receptor 1 (TLR1), TLR6, and TLR10 locus to cytokine production in response to C. trachomatis. We determined that a single-nucleotide polymorphism (SNP) (rs1057807), located in a region that forms a loop with the TLR6 promoter, is associated with increased expression of TLR1, TLR6, and TLR10 and secreted levels of ten C. trachomatis-induced cytokines. Production of these C. trachomatis-induced cytokines is primarily dependent on MyD88 and TLR6 based on experiments using inhibitors, blocking antibodies, RNAi, and protein overexpression. Population genetic analyses further demonstrated that the mean IL-6 response of cells from two European populations were higher than the mean response of cells from three African populations and that this difference was partially attributable to variation in rs1057807 allele frequency. In contrast, a SNP associated with a different pro-inflammatory cytokine (rs2869462 associated with the chemokine CXCL10) exhibited an opposite response, underscoring the complexity of how different genetic variants contribute to an individual's immune response. This multidisciplinary study has identified a long-range chromatin interaction and genetic variation that regulates TLR6 to broaden our understanding of how human genetic variation affects the C. trachomatis-induced immune response.

Full Text

Duke Authors

Cited Authors

  • Barnes, AB; Keener, RM; Schott, BH; Wang, L; Valdivia, RH; Ko, DC

Published Date

  • January 13, 2022

Published In

  • Hgg Adv

Volume / Issue

  • 3 / 1

Start / End Page

  • 100071 -

PubMed ID

  • 35047856

Pubmed Central ID

  • PMC8756536

Electronic International Standard Serial Number (EISSN)

  • 2666-2477

Digital Object Identifier (DOI)

  • 10.1016/j.xhgg.2021.100071

Language

  • eng

Conference Location

  • United States