Association of human TLR1 and TLR6 deficiency with altered immune responses to BCG vaccination in South African infants

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dc.contributor.authorRandhawa, April Kauren_ZA
dc.contributor.authorShey, Muki Sen_ZA
dc.contributor.authorKeyser, Alanaen_ZA
dc.contributor.authorPeixoto, Blasen_ZA
dc.contributor.authorWells, Richard Den_ZA
dc.contributor.authorde Kock, Marwouen_ZA
dc.contributor.authorLerumo, Lesedien_ZA
dc.contributor.authorHughes, Janeen_ZA
dc.contributor.authorHussey, Gregoryen_ZA
dc.contributor.authorHawkridge, Anthonyen_ZA
dc.contributor.authorKaplan, Gillaen_ZA
dc.contributor.authorHanekom, Willem Aen_ZA
dc.contributor.authorHawn, Thomas Ren_ZA
dc.date.accessioned2016-01-11T06:52:16Z
dc.date.available2016-01-11T06:52:16Z
dc.date.issued2011en_ZA
dc.description.abstractThe 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.en_ZA
dc.identifier.apacitationRandhawa, A. K., Shey, M. S., Keyser, A., Peixoto, B., Wells, R. D., de Kock, M., ... Hawn, T. R. (2011). Association of human TLR1 and TLR6 deficiency with altered immune responses to BCG vaccination in South African infants. <i>PLoS One</i>, http://hdl.handle.net/11427/16262en_ZA
dc.identifier.chicagocitationRandhawa, April Kaur, Muki S Shey, Alana Keyser, Blas Peixoto, Richard D Wells, Marwou de Kock, Lesedi Lerumo, et al "Association of human TLR1 and TLR6 deficiency with altered immune responses to BCG vaccination in South African infants." <i>PLoS One</i> (2011) http://hdl.handle.net/11427/16262en_ZA
dc.identifier.citationRandhawa, A. K., Shey, M. S., Keyser, A., Peixoto, B., Wells, R. D., de Kock, M., ... & Kaplan, G. (2011). Association of human TLR1 and TLR6 deficiency with altered immune responses to BCG vaccination in South African infants. PLoS Pathog, 7(8), e1002174. doi:10.1371/journal.ppat.1002174en_ZA
dc.identifier.ris TY - Journal Article AU - Randhawa, April Kaur AU - Shey, Muki S AU - Keyser, Alana AU - Peixoto, Blas AU - Wells, Richard D AU - de Kock, Marwou AU - Lerumo, Lesedi AU - Hughes, Jane AU - Hussey, Gregory AU - Hawkridge, Anthony AU - Kaplan, Gilla AU - Hanekom, Willem A AU - Hawn, Thomas R AB - 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. DA - 2011 DB - OpenUCT DO - 10.1371/journal.ppat.1002174 DP - University of Cape Town J1 - PLoS One LK - https://open.uct.ac.za PB - University of Cape Town PY - 2011 T1 - Association of human TLR1 and TLR6 deficiency with altered immune responses to BCG vaccination in South African infants TI - Association of human TLR1 and TLR6 deficiency with altered immune responses to BCG vaccination in South African infants UR - http://hdl.handle.net/11427/16262 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/16262
dc.identifier.urihttp://dx.doi.org/10.1371/journal.ppat.1002174
dc.identifier.vancouvercitationRandhawa AK, Shey MS, Keyser A, Peixoto B, Wells RD, de Kock M, et al. Association of human TLR1 and TLR6 deficiency with altered immune responses to BCG vaccination in South African infants. PLoS One. 2011; http://hdl.handle.net/11427/16262.en_ZA
dc.language.isoengen_ZA
dc.publisherPublic Library of Scienceen_ZA
dc.publisher.departmentSouth African Tuberculosis Vaccine Initiative (SATVI)en_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_ZA
dc.rights.holder© 2011 Randhawa et alen_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/4.0en_ZA
dc.sourcePLoS Oneen_ZA
dc.source.urihttp://journals.plos.org/plospathogensen_ZA
dc.subject.otherCytokinesen_ZA
dc.subject.otherT cellsen_ZA
dc.subject.otherImmune responseen_ZA
dc.subject.otherVaccination and immunizationen_ZA
dc.subject.otherInfantsen_ZA
dc.subject.otherBlooden_ZA
dc.subject.otherMycobacterium tuberculosisen_ZA
dc.subject.otherTuberculosisen_ZA
dc.titleAssociation of human TLR1 and TLR6 deficiency with altered immune responses to BCG vaccination in South African infantsen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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