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.

Interleukin-7 receptor gene polymorphism at +1237 locus and its effect on susceptibility to opportunistic infections among HIV and AIDS patients in Limpopo Province, South Africa

“…Similarly, Verma et al (2012) found that the C allele of the IL-12Rβ2 promoter significantly impacted TB among Indian patients. Randhawa et al (2011) conducted a different study in South Africa and found that TLR1/6 polymorphisms modulate Th1 T-cell polarization through genetic regulation of monocyte IL-10 secretion in the absence of IL-1 among TB patients. This is the first time that the IL-7Rα +1237 genotypes have been associated with general symptoms such as chest pain.…”

Immunological evaluation of a novel Mycobacterium tuberculosis antigen, Rv3117, absent in Mycobacterium bovis BCG

“…Although it has been suggested that the explanation regarding differences in strains may be discounted, as parallel studies in the UK and Malawi using the same strain of vaccine still showed differences in efficacy (8), Keyser et al (25) revealed that BCG substrains had the capacity to drive Th2 immunity and induced variable protection against M. tuberculosis infection (25). Moreover, further study is required with regard to host genetics, as human Toll-like receptor 1 (TLR1) and TLR6-deficiency altered immune responses to BCG vaccination in South African infants (26). In adults and adolescents, pre-exposure to environmental mycobacteria is likely to influence immune responses (27).…”

Genetics of leprosy reactions: an overview

“…While the G allele (serine) is rare, or entirely absent in Africans and Asians, it is the major allele in populations of European descendant (Wong et al 2010). The polymorphism has also been associated with susceptibility to clinical outcomes of malaria (Leoratti et al 2008) and an altered immune response to BCG vaccination, with the same risk allele (Randhawa et al 2011). …”