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Association of Human TLR1 and TLR6 Deficiency with Altered Immune Responses to BCG Vaccination in South African Infants


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.


Vyšlo v časopise: Association of Human TLR1 and TLR6 Deficiency with Altered Immune Responses to BCG Vaccination in South African Infants. PLoS Pathog 7(8): e32767. doi:10.1371/journal.ppat.1002174
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002174

Souhrn

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.


Zdroje

1. WHO 2006 World Health Organization, Global Tuberculosis Control: Surveillance, Planning, Financing. Geneva

2. ColditzGABerkeyCSMostellerFBrewerTFWilsonME 1995 The Efficacy of Bacillus Calmette-Guerin Vaccination of Newborns and Infants in the Prevention of Tuberculosis: Meta-Analyses of the Published Literature. Pediatrics 96 29 35

3. ColditzGABrewerTFBerkeyCSWilsonMEBurdickE 1994 Efficacy of BCG Vaccine in the Prevention of Tuberculosis: Meta-analysis of the Published Literature. JAMA 271 698 702

4. BlackGDockrellHCrampinAFloydSWeirR 2001 Patterns and Implications of Naturally Acquired Immune Responses to Environmental and Tuberculous Mycobacterial Antigens in Northern Malawi. J Infect Dis 184 322 329

5. BlackGFRosemaryEWFloydSBlissLWarndorffDK 2002 BCG-induced increase in interferon-gamma response to mycobacterial antigens and efficacy of BCG vaccination in Malawi and the UK: two randomised controlled studies. LANCET 359 1393 1401

6. LagranderieMRBalazucAMDeriaudELeclercCDGheorghiuM 1996 Comparison of immune responses of mice immunized with five different Mycobacterium bovis BCG vaccine strains. Infect Immun 64 1 9

7. van der EijkEAvan de VosseEVandenbrouckeJPvan DisselJT 2007 Heredity versus Environment in Tuberculosis in Twins: The 1950s United Kingdom Prophit Survey Simonds and Comstock Revisited. Am J Respir Crit Care Med 176 1281 1288

8. FortinAAbelLCasanovaJLGrosP 2007 Host Genetics of Mycobacterial Diseases in Mice and Men: Forward Genetic Studies of BCG-osis and Tuberculosis. Annu Rev of Genomics Hum Genet 8 163 192

9. VannbergFOChapmanSJHillAV 2011 Human genetic susceptibility to intracellular pathogens. Immunol Rev 240 105 116

10. BerringtonWRHawnTR 2007 Mycobacterium tuberculosis, macrophages, and the innate immune response: does common variation matter? Immunol Rev 219 167 186

11. Thye T, Vannberg FO, Wong SH, Owusu-Dabo E, Osei I, et al. Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2. Nat Genet 42 739 741

12. CobatAGallantCJSimkinLBlackGFStanleyK 2009 Two loci control tuberculin skin test reactivity in an area hyperendemic for tuberculosis. J Exp Med 206 2583 2591

13. SepulvedaRLHeibaIMKingAGonzalezBElstonRC 1994 Evaluation of tuberculin reactivity in BCG-immunized siblings. Am J Respir Crit Care Med 149 620 624

14. SteinCMZalwangoSMaloneLLWonSMayanja-KizzaH 2008 Genome Scan of M. tuberculosis Infection and Disease in Ugandans. PLoS ONE 3 e4094

15. CobatAGallant CarolineJSimkinLBlack GillianFStanleyK 2010 High Heritability of Antimycobacterial Immunity in an Area of Hyperendemicity for Tuberculosis Disease. J Infect Dis 201 15 19

16. JepsonAFowlerABanyaWSinghMBennettS 2001 Genetic Regulation of Acquired Immune Responses to Antigens of Mycobacterium tuberculosis: a Study of Twins in West Africa. Infect Immun 69 3989 3994

17. Stein CatherineMGuwatuddeDNakakeetoMPetersPElston RobertC 2003 Heritability Analysis of Cytokines as Intermediate Phenotypes of Tuberculosis. J Infect Dis 187 1679 1685

18. FinanCOtaMOCMarchantANewportMJ 2008 Natural Variation in Immune Responses to Neonatal Mycobacterium bovis Bacillus Calmette-Guerin (BCG) Vaccination in a Cohort of Gambian Infants. PLoS ONE 3 e3485

19. LalorMBen-SmithAGorak-StolinskaPWeirRFloydS 2009 Population Differences in Immune Responses to Bacille Calmette-Guérin Vaccination in Infancy. J Infect Dis 199 795 800

20. MischEAHawnTR 2008 Toll-like receptor polymorphisms and susceptibility to human disease. Clin Sci 114 347 360

21. RandhawaAKHawnTR 2008 Toll-like receptors: their roles in bacterial recognition and respiratory infections. Expert Rev Anti Infect Ther 6 479 495

22. MedzhitovRPreston-HurlburtPJanewayCA 1997 A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388 394 397

23. KawaiTAkiraS The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11 373 384

24. IwasakiAMedzhitovR Regulation of Adaptive Immunity by the Innate Immune System. Science 327 291 295

25. ManicassamySPulendranB 2009 Modulation of adaptive immunity with Toll-like receptors. Semin Immunol. 21 185 193

26. JohnsonCMLyleEAOmuetiKOStepenskyVAYeginO 2007 Cutting Edge: A Common Polymorphism Impairs Cell Surface Trafficking and Functional Responses of TLR1 but Protects against Leprosy. J Immunol 178 7520 7524

27. Hawn ThomasRMischEADunstan SarahJThwaites GuyELan NguyenTN 2007 A common human TLR1 polymorphism regulates the innate immune response to lipopeptides. Eur J Immunol 37 2280 2289

28. MischEMacDonaldMRanjitCSapkotaBSiddiquiM 2008 Human TLR 1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction. PLoS Negl Trop Dis 2 e231

29. OgusACYoldasBOzdemirTUguzAOlcenS 2004 The Arg753Gln polymorphism of the human Toll-like receptor 2 gene in tuberculosis disease. Eur Respir J 23 219 223

30. SchroderNWJDiterichIZinkeAEckertJDraingC 2005 Heterozygous Arg753Gln Polymorphism of Human TLR-2 Impairs Immune Activation by Borrelia burgdorferi and Protects from Late Stage Lyme Disease. J Immunol 175 2534 2540

31. LorenzEMiraJPCornishKLArbourNCSchwartzDA 2000 A Novel Polymorphism in the Toll-Like Receptor 2 Gene and Its Potential Association with Staphylococcal Infection. Infect Immun 68 6398 6401

32. KhorCCChapmanSJVannbergFODunneAMurphyC 2007 A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nat Genet 39 523 528

33. SheyMSRandhawaAKBowmakerMSmithEScribaTJ 2010 Single nucleotide polymorphisms in toll-like receptor 6 are associated with altered lipopeptide- and mycobacteria-induced interleukin-6 secretion. Genes Immun 11 561 572

34. WurfelMMGordonACHoldenTDRadellaFStroutJ 2008 Toll-like Receptor 1 Polymorphisms Affect Innate Immune Responses and Outcomes in Sepsis. Am J Respir Crit Care Med 178 710 720

35. ArbourNCLorenzESchutteBCZabnerJKlineJN 2000 TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 25 187 191

36. HawnTRVerbonALettingaKDZhaoLPLiSS 2003 A Common Dominant TLR5 Stop Codon Polymorphism Abolishes Flagellin Signaling and Is Associated with Susceptibility to Legionnaires' Disease. J Exp Med 198 1563 1572

37. HawnTRVerbonAJanerMZhaoLPBeutlerB 2005 Toll-like receptor 4 polymorphisms are associated with resistance to Legionnaires' disease. Proc Natl Acad Sci U S A 102 2487 2489

38. HawnTDunstanSThwaitesGSimmonsCThuongN 2006 A Polymorphism in Toll-Interleukin 1 Receptor Domain Containing Adaptor Protein Is Associated with Susceptibility to Meningeal Tuberculosis. J Infect Dis 194 1127 1134

39. BarreiroLBNeyrollesOBabbCLTailleuxLQuachH 2006 Promoter variation in the DC-SIGN-encoding gene CD209 is associated with tuberculosis. PLoS Med 3 e20

40. MaXLiuYGowenBBGravissEAClarkAG 2007 Full-Exon Resequencing Reveals Toll-Like Receptor Variants Contribute to Human Susceptibility to Tuberculosis Disease. PLoS ONE 2 e1318

41. OmuetiKOMazurDJThompsonKSLyleEATappingRI 2007 The Polymorphism P315L of Human Toll-Like Receptor 1 Impairs Innate Immune Sensing of Microbial Cell Wall Components. J Immunol 178 6387 6394

42. WeirREBlackGFNazarethBFloydSStensonS 2006 The influence of previous exposure to environmental mycobacteria on the interferon-gamma response to bacille Calmette–Guérin vaccination in southern England and northern Malawi. Clin Exp Immunol 146 390 399

43. NewportMJAllenAAwomoyiAADunstanSJMcKinneyE 2004 The toll-like receptor 4 Asp299Gly variant: no influence on LPS responsiveness or susceptibility to pulmonary tuberculosis in The Gambia. Tuberculosis 84 347 352

44. WongSHGochhaitSMalhotraDPetterssonFHTeoYY 2010 Leprosy and the Adaptation of Human Toll-Like Receptor 1. PLoS Pathog 6 e1000979

45. LyakhLTrinchieriGProvezzaLCarraGGerosaF 2008 Regulation of interleukin-12/interleukin-23 production and the T-helper 17 response in humans. Immunol Rev 226 112 131

46. D'AndreaAAste-AmezagaMValianteNMMaXKubinM 1993 Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J Exp Med 178 1041 1048

47. RedfordPSMurrayPJO'GarraA 2011 The role of IL-10 in immune regulation during M. tuberculosis infection. Mucosal Immunol 4 261 270

48. MedzhitovRHorngT 2009 Transcriptional control of the inflammatory response. Nat Rev Immunol 9 692 703

49. BaliP 2004 Modulating vaccine responses with dendritic cells and Toll-like receptors. Immunol Rev 199 227 250

50. PulendranB 2005 Variegation of the Immune Response with Dendritic Cells and Pathogen Recognition Receptors. J Immunol 174 2457 2465

51. ErnstJD 1998 Macrophage Receptors for Mycobacterium tuberculosis. Infect Immun 66 1277 1281

52. RandhawaAKZiltenerHJMerzabanJSStokesRW 2005 CD43 Is Required for Optimal Growth Inhibition of Mycobacterium tuberculosis in Macrophages and in Mice. J Immunol 175 1805 1812

53. RandhawaAKZiltenerHJStokesRW 2008 CD43 controls the intracellular growth of Mycobacterium tuberculosis through the induction of TNF-α-mediated apoptosis. Cell Microbiol 10 2105 2117

54. IshikawaEIshikawaTMoritaYSToyonagaKYamadaH 2009 Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle. J Exp Med 206 2879 2888

55. BrownGD 2006 Dectin-1: a signalling non-TLR pattern-recognition receptor. Nat Rev Immunol 6 33 43

56. YadavMSchoreyJS 2006 The beta-glucan receptor dectin-1 functions together with TLR2 to mediate macrophage activation by mycobacteria. Blood 108 3168 3175

57. WatkinsMLVSemplePLAbelBHanekomWAKaplanG 2008 Exposure of Cord Blood to Mycobacterium bovis BCG Induces an Innate Response but Not a T-Cell Cytokine Response. Clin Vaccine Immunol 15 1666 1673

58. HanekomWAHughesJMavinkurveMMendilloMWatkinsM 2004 Novel application of a whole blood intracellular cytokine detection assay to quantitate specific T-cell frequency in field studies. J Immunol Methods 291 185 195

59. CasanovaJ-LAbelL 2002 Genetic Dissection of Immunity to Mycobacteria: The Human Model. Annu Rev Immunol 20 581 620

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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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