title: Association of human TLR1 and TLR6 deficiency with altered immune responses to BCG vaccination in South African infants.
abstract: The development of effective immunoprophylaxis against tuberculosis (TB) remains a global priority, but is hampered by a partially protective Bacillus Calmette-Guérin (BCG) vaccine and an incomplete understanding of the mechanisms of immunity to Mycobacterium tuberculosis. Although host genetic factors may be a primary reason for BCG's variable and inadequate efficacy, this possibility has not been intensively examined. We hypothesized that Toll-like receptor (TLR) variation is associated with altered in vivo immune responses to BCG. We examined whether functionally defined TLR pathway polymorphisms were associated with T cell cytokine responses in whole blood stimulated ex vivo with BCG 10 weeks after newborn BCG vaccination of South African infants. In the primary analysis, polymorphism TLR6_C745T (P249S) was associated with increased BCG-induced IFN-γ in both discovery (n = 240) and validation (n = 240) cohorts. In secondary analyses of the combined cohort, TLR1_T1805G (I602S) and TLR6_G1083C (synonymous) were associated with increased IFN-γ, TLR6_G1083C and TLR6_C745T were associated with increased IL-2, and TLR1_A1188T was associated with increased IFN-γ and IL-2. For each of these polymorphisms, the hypo-responsive allele, as defined by innate immunity signaling assays, was associated with increased production of TH1-type T cell cytokines (IFN-γ or IL-2). After stimulation with TLR1/6 lipopeptide ligands, PBMCs from TLR1/6-deficient individuals (stratified by TLR1_T1805G and TLR6_C745T hyporesponsive genotypes) secreted lower amounts of IL-6 and IL-10 compared to those with responsive TLR1/6 genotypes. In contrast, no IL-12p70 was secreted by PBMCs or monocytes. These data support a mechanism where TLR1/6 polymorphisms modulate TH1 T-cell polarization through genetic regulation of monocyte IL-10 secretion in the absence of IL-12. These studies provide evidence that functionally defined innate immune gene variants are associated with the development of adaptive immune responses after in vivo vaccination against a bacterial pathogen in humans. These findings could potentially guide novel adjuvant vaccine strategies as well as have implications for IFN-γ-based diagnostic testing for TB.
authors.affiliation: Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: April Kaur
authors.initials: AK
authors.lastname: Randhawa
authors.forename: Muki S
authors.initials: MS
authors.lastname: Shey
authors.forename: Alana
authors.initials: A
authors.lastname: Keyser
authors.forename: Blas
authors.initials: B
authors.lastname: Peixoto
authors.forename: Richard D
authors.initials: RD
authors.lastname: Wells
authors.forename: Marwou
authors.initials: M
authors.lastname: de Kock
authors.forename: Lesedi
authors.initials: L
authors.lastname: Lerumo
authors.forename: Jane
authors.initials: J
authors.lastname: Hughes
authors.forename: Gregory
authors.initials: G
authors.lastname: Hussey
authors.forename: Anthony
authors.initials: A
authors.lastname: Hawkridge
authors.forename: Gilla
authors.initials: G
authors.lastname: Kaplan
authors.forename: Willem A
authors.initials: WA
authors.lastname: Hanekom
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Hawn
mesh_terms: D001500:BCG Vaccine / Q000276:immunology*; D006801:Humans; D007223:Infant; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D009163:Mycobacterium bovis / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology; D011110:Polymorphism, Genetic; D051194:Toll-Like Receptor 1 / Q000172:deficiency* / Q000235:genetics; D051216:Toll-Like Receptor 6 / Q000172:deficiency* / Q000235:genetics; D014376:Tuberculosis / Q000517:prevention & control*
chemical_list: D001500:BCG Vaccine; D007376:Interleukin-2; D015850:Interleukin-6; C495368:TLR6 protein, human; D051194:Toll-Like Receptor 1; D051216:Toll-Like Receptor 6; D007371:Interferon-gamma