You are here
Association of human TLR1 and TLR6 deficiency with altered immune responses to BCG vaccination in South African infants.
Title | Association of human TLR1 and TLR6 deficiency with altered immune responses to BCG vaccination in South African infants. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Randhawa, AKaur, Shey, MS, Keyser, A, Peixoto, B, Wells, RD, de Kock, M, Lerumo, L, Hughes, J, Hussey, G, Hawkridge, A, Kaplan, G, Hanekom, WA, Hawn, TR |
Corporate Authors | South African Tuberculosis Vaccine Initiative Team |
Journal | PLoS Pathog |
Volume | 7 |
Issue | 8 |
Pagination | e1002174 |
Date Published | 2011 Aug |
ISSN | 1553-7374 |
Keywords | BCG Vaccine, Humans, Infant, Interferon-gamma, Interleukin-2, Interleukin-6, Mycobacterium bovis, Mycobacterium tuberculosis, Polymorphism, Genetic, Toll-Like Receptor 1, Toll-Like Receptor 6, Tuberculosis |
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. |
DOI | 10.1371/journal.ppat.1002174 |
Alternate Journal | PLoS Pathog. |
PubMed ID | 21852947 |