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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Association of human TLR1 and TLR6 deficiency with altered immune responses to bcg vaccination in south african infants
PLoS Pathogens, Volume 7, No. 8, Article e1002174, Year 2011
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Description
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. © 2011 Randhawa et al.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3154845/bin/ppat.1002174.s001.tif
https://efashare.b-cdn.net/share/pmc/articles/PMC3154845/bin/ppat.1002174.s002.tif
https://efashare.b-cdn.net/share/pmc/articles/PMC3154845/bin/ppat.1002174.s003.docx
https://efashare.b-cdn.net/share/pmc/articles/PMC3154845/bin/ppat.1002174.s004.docx
https://efashare.b-cdn.net/share/pmc/articles/PMC3154845/bin/ppat.1002174.s005.docx
Authors & Co-Authors
Randhawa, April Kaur
United States, Seattle
University of Washington School of Medicine
Shey, Muki Shehu
South Africa, Observatory
South African Tuberculosis Vaccine Initiative
Keyser, Alana T.
South Africa, Observatory
South African Tuberculosis Vaccine Initiative
Peixoto, Blas
United States, Newark
Public Health Research Institute
Wells, Richard D.
United States, Seattle
University of Washington School of Medicine
de Kock, Marwou
South Africa, Observatory
South African Tuberculosis Vaccine Initiative
Lerumo, Lesedi
South Africa, Observatory
South African Tuberculosis Vaccine Initiative
Hughes, Jane E.
South Africa, Observatory
South African Tuberculosis Vaccine Initiative
Hussey, Greg Dudley
South Africa, Observatory
South African Tuberculosis Vaccine Initiative
Hawkridge, Anthony J.
South Africa, Observatory
South African Tuberculosis Vaccine Initiative
Kaplan, Gilla
United States, Newark
Public Health Research Institute
Hanekom, Willem Albert
South Africa, Observatory
South African Tuberculosis Vaccine Initiative
Hawn, Thomas Richard
United States, Seattle
University of Washington School of Medicine
Statistics
Citations: 88
Authors: 13
Affiliations: 3
Identifiers
Doi:
10.1371/journal.ppat.1002174
ISSN:
15537366
e-ISSN:
15537374
Research Areas
Genetics And Genomics
Infectious Diseases
Study Design
Cohort Study