Skip to main content

Advertisement

SpringerLink
Log in

Polymorphisms in Toll-like receptor 4 (TLR4) are associated with protection against leprosy

  • Article
  • Published:
European Journal of Clinical Microbiology & Infectious Diseases Aims and scope Submit manuscript

Abstract

Accumulating evidence suggests that polymorphisms in Toll-like receptors (TLRs) influence the pathogenesis of mycobacterial infections, including leprosy, a disease whose manifestations depend on host immune responses. Polymorphisms in TLR2 are associated with an increased risk of reversal reaction, but not susceptibility to leprosy itself. We examined whether polymorphisms in TLR4 are associated with susceptibility to leprosy in a cohort of 441 Ethiopian leprosy patients and 197 healthy controls. We found that two single nucleotide polymorphisms (SNPs) in TLR4 (896G>A [D299G] and 1196C>T [T399I]) were associated with a protective effect against the disease. The 896GG, GA and AA genotypes were found in 91.7, 7.8 and 0.5% of leprosy cases versus 79.9, 19.1 and 1.0% of controls, respectively (odds ratio [OR] = 0.34, 95% confidence interval [CI] 0.20–0.57, P < 0.001, additive model). Similarly, the 1196CC, CT and TT genotypes were found in 98.1, 1.9 and 0% of leprosy cases versus 91.8, 7.7 and 0.5% of controls, respectively (OR = 0.16, 95% CI 0.06-–.40, P < 0.001, dominant model). We found that Mycobacterium leprae stimulation of monocytes partially inhibited their subsequent response to lipopolysaccharide (LPS) stimulation. Our data suggest that TLR4 polymorphisms are associated with susceptibility to leprosy and that this effect may be mediated at the cellular level by the modulation of TLR4 signalling by M. leprae.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. [No authors listed] (2007) Global leprosy situation, 2007. Wkly Epidemiol Rec 82:225–232

    Google Scholar 

  2. Ridley DS, Jopling WH (1966) Classification of leprosy according to immunity. A five-group system. Int J Lepr Other Mycobact Dis 34:255–273

    PubMed  CAS  Google Scholar 

  3. Scollard DM, Adams LB, Gillis TP et al (2006) The continuing challenges of leprosy. Clin Microbiol Rev 19:338–381. doi:10.1128/CMR.19.2.338-381.2006

    Article  PubMed  CAS  Google Scholar 

  4. Yamamura M, Uyemura K, Deans RJ et al (1991) Defining protective responses to pathogens: cytokine profiles in leprosy lesions. Science 254:277–279. doi:10.1126/science.1925582

    Article  PubMed  CAS  Google Scholar 

  5. Salgame P, Abrams JS, Clayberger C et al (1991) Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science 254:279–282. doi:10.1126/science.1681588

    Article  PubMed  CAS  Google Scholar 

  6. Bochud PY, Bochud M, Telenti A et al (2007) Innate immunogenetics: a tool for exploring new frontiers of host defence. Lancet Infect Dis 7:531–542. doi:10.1016/S1473-3099(07)70185-8

    Article  PubMed  CAS  Google Scholar 

  7. Iwasaki A, Medzhitov R (2004) Toll-like receptor control of the adaptive immune responses. Nat Immunol 5:987–995. doi:10.1038/ni1112

    Article  PubMed  CAS  Google Scholar 

  8. Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801. doi:10.1016/j.cell.2006.02.015

    Article  PubMed  CAS  Google Scholar 

  9. Quesniaux V, Fremond C, Jacobs M et al (2004) Toll-like receptor pathways in the immune responses to mycobacteria. Microbes Infect 6:946–959. doi:10.1016/j.micinf.2004.04.016

    Article  PubMed  CAS  Google Scholar 

  10. Jo EK, Yang CS, Choi CH et al (2007) Intracellular signalling cascades regulating innate immune responses to Mycobacteria: branching out from Toll-like receptors. Cell Microbiol 9:1087–1098. doi:10.1111/j.1462-5822.2007.00914.x

    Article  PubMed  CAS  Google Scholar 

  11. Heldwein KA, Fenton MJ (2002) The role of Toll-like receptors in immunity against mycobacterial infection. Microbes Infect 4:937–944. doi:10.1016/S1286-4579(02)01611-8

    Article  PubMed  CAS  Google Scholar 

  12. Krutzik SR, Ochoa MT, Sieling PA et al (2003) Activation and regulation of Toll-like receptors 2 and 1 in human leprosy. Nat Med 9:525–532. doi:10.1038/nm864

    Article  PubMed  CAS  Google Scholar 

  13. Means TK, Wang S, Lien E et al (1999) Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis. J Immunol 163:3920–3927

    PubMed  CAS  Google Scholar 

  14. Alcaïs A, Mira M, Casanova JL et al (2005) Genetic dissection of immunity in leprosy. Curr Opin Immunol 17:44–48. doi:10.1016/j.coi.2004.11.006

    Article  PubMed  CAS  Google Scholar 

  15. Alcaïs A, Alter A, Antoni G et al (2007) Stepwise replication identifies a low-producing lymphotoxin-alpha allele as a major risk factor for early-onset leprosy. Nat Genet 39:517–522. doi:10.1038/ng2000

    Article  PubMed  CAS  Google Scholar 

  16. Santos AR, Suffys PN, Vanderborght PR et al (2002) Role of tumor necrosis factor-alpha and interleukin-10 promoter gene polymorphisms in leprosy. J Infect Dis 186:1687–1691. doi:10.1086/345366

    Article  PubMed  CAS  Google Scholar 

  17. Moraes MO, Pacheco AG, Schonkeren JJ et al (2004) Interleukin-10 promoter single-nucleotide polymorphisms as markers for disease susceptibility and disease severity in leprosy. Genes Immun 5:592–595. doi:10.1038/sj.gene.6364122

    Article  PubMed  CAS  Google Scholar 

  18. Mira MT (2006) Genetic host resistance and susceptibility to leprosy. Microbes Infect 8:1124–1131. doi:10.1016/j.micinf.2005.10.024

    Article  PubMed  CAS  Google Scholar 

  19. Misch EA, Hawn TR (2008) Toll-like receptor polymorphisms and susceptibility to human disease. Clin Sci (Lond) 114:347–360. doi:10.1042/CS20070214

    Article  Google Scholar 

  20. Bochud PY, Hawn TR, Siddiqui MR et al (2008) Toll-like receptor 2 (TLR2) polymorphisms are associated with reversal reaction in leprosy. J Infect Dis 197:253–261. doi:10.1086/524688

    Article  PubMed  CAS  Google Scholar 

  21. Ferwerda B, Kibiki GS, Netea MG et al (2007) The toll-like receptor 4 Asp299Gly variant and tuberculosis susceptibility in HIV-infected patients in Tanzania. AIDS 21:1375–1377. doi:10.1097/QAD.0b013e32814e6b2d

    Article  PubMed  CAS  Google Scholar 

  22. Bochud PY, Chien JW, Marr KA et al (2008) Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med 359:1766–1777. doi:10.1056/NEJMoa0802629

    Article  PubMed  CAS  Google Scholar 

  23. Arbour NC, Lorenz E, Schutte BC et al (2000) TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 25:187–191. doi:10.1038/76048

    Article  PubMed  CAS  Google Scholar 

  24. Saunderson P, Gebre S, Desta K et al (2000) The ALERT MDT Field Evaluation Study (AMFES): a descriptive study of leprosy in Ethiopia. Patients, methods and baseline characteristics. Lepr Rev 71:273–284

    PubMed  CAS  Google Scholar 

  25. Jopling WH (1981) A practical classification of leprosy for field workers. Lepr Rev 52:273

    Google Scholar 

  26. Saunderson P, Gebre S, Byass P (2000) Reversal reactions in the skin lesions of AMFES patients: incidence and risk factors. Lepr Rev 71:309–317

    PubMed  CAS  Google Scholar 

  27. Gordon D, Abajian C, Green P (1998) Consed: a graphical tool for sequence finishing. Genome Res 8:195–202

    PubMed  CAS  Google Scholar 

  28. Hawn TR, Dunstan SJ, Thwaites GE et al (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. doi:10.1086/507907

    Article  PubMed  CAS  Google Scholar 

  29. Turvey SE, Hawn TR (2006) Towards subtlety: understanding the role of Toll-like receptor signaling in susceptibility to human infections. Clin Immunol 120:1–9. doi:10.1016/j.clim.2006.02.003

    Article  PubMed  CAS  Google Scholar 

  30. S.A.G.E. Statistical Analysis for Genetic Epidemiology. Case Western Reserve University. 5.0 edn, 2005

  31. Lahiri R, Randhawa B, Krahenbuhl J (2005) Application of a viability-staining method for Mycobacterium leprae derived from the athymic (nu/nu) mouse foot pad. J Med Microbiol 54:235–242. doi:10.1099/jmm.0.45700-0

    Article  PubMed  Google Scholar 

  32. Suzuki K, Fukutomi Y, Matsuoka M et al (1993) Differential production of interleukin 1 (IL-1), IL-6, tumor necrosis factor, and IL-1 receptor antagonist by human monocytes stimulated with Mycobacterium leprae and M. bovis BCG. Int J Lepr Other Mycobact Dis 61:609–618

    PubMed  CAS  Google Scholar 

  33. Murray RA, Siddiqui MR, Mendillo M et al (2007) Mycobacterium leprae inhibits dendritic cell activation and maturation. J Immunol 178:338–344

    PubMed  CAS  Google Scholar 

  34. Ferwerda B, McCall MB, Alonso S et al (2007) TLR4 polymorphisms, infectious diseases, and evolutionary pressure during migration of modern humans. Proc Natl Acad Sci USA 104:16645–16650. doi:10.1073/pnas.0704828104

    Article  PubMed  Google Scholar 

  35. Bochud PY, Hawn TR, Aderem A (2003) Cutting edge: a Toll-like receptor 2 polymorphism that is associated with lepromatous leprosy is unable to mediate mycobacterial signaling. J Immunol 170:3451–3454

    PubMed  CAS  Google Scholar 

  36. Misch EA, Macdonald M, Ranjit C et al (2008) Human TLR1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction. PLoS Negl Trop Dis 2:e231. doi:10.1371/journal.pntd.0000231

    Article  PubMed  CAS  Google Scholar 

  37. Johnson CM, Lyle EA, Omueti KO et al (2007) Cutting edge: A common polymorphism impairs cell surface trafficking and functional responses of TLR1 but protects against leprosy. J Immunol 178:7520–7524

    PubMed  CAS  Google Scholar 

  38. Hawn TR, Misch EA, Dunstan SJ et al (2007) A common human TLR1 polymorphism regulates the innate immune response to lipopeptides. Eur J Immunol 37:2280–2289

    Article  PubMed  CAS  Google Scholar 

  39. Kang TJ, Chae GT (2001) Detection of Toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients. FEMS Immunol Med Microbiol 31:53–58. doi:10.1111/j.1574-695X.2001.tb01586.x

    Article  PubMed  CAS  Google Scholar 

  40. Malhotra D, Relhan V, Reddy BS et al (2005) TLR2 Arg677Trp polymorphism in leprosy: revisited. Hum Genet 116:413–415. doi:10.1007/s00439-004-1249-9

    Article  PubMed  CAS  Google Scholar 

  41. Yim JJ, Ding L, Schäffer AA et al (2004) A microsatellite polymorphism in intron 2 of human Toll-like receptor 2 gene: functional implications and racial differences. FEMS Immunol Med Microbiol 40:163–169. doi:10.1016/S0928-8244(03)00342-0

    Article  PubMed  CAS  Google Scholar 

  42. Ogus AC, Yoldas B, Ozdemir T et al (2004) The Arg753GLn polymorphism of the human toll-like receptor 2 gene in tuberculosis disease. Eur Respir J 23:219–223. doi:10.1183/09031936.03.00061703

    Article  PubMed  CAS  Google Scholar 

  43. Schröder NW, Diterich I, Zinke A et al (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

    PubMed  Google Scholar 

  44. Hawn TR, Verbon A, Janer M et al (2005) Toll-like receptor 4 polymorphisms are associated with resistance to Legionnaires’ disease. Proc Natl Acad Sci USA 102:2487–2489. doi:10.1073/pnas.0409831102

    Article  PubMed  CAS  Google Scholar 

  45. Michel O, LeVan TD, Stern D et al (2003) Systemic responsiveness to lipopolysaccharide and polymorphisms in the toll-like receptor 4 gene in human beings. J Allergy Clin Immunol 112:923–929. doi:10.1016/j.jaci.2003.05.001

    Article  PubMed  CAS  Google Scholar 

  46. Fagerås Böttcher M, Hmani-Aifa M, Lindström A et al (2004) A TLR4 polymorphism is associated with asthma and reduced lipopolysaccharide-induced interleukin-12(p70) responses in Swedish children. J Allergy Clin Immunol 114:561–567. doi:10.1016/j.jaci.2004.04.050

    Article  PubMed  CAS  Google Scholar 

  47. Erridge C, Stewart J, Poxton IR (2003) Monocytes heterozygous for the Asp299Gly and Thr399Ile mutations in the Toll-like receptor 4 gene show no deficit in lipopolysaccharide signalling. J Exp Med 197:1787–1791. doi:10.1084/jem.20022078

    Article  PubMed  CAS  Google Scholar 

  48. von Aulock S, Schröder NW, Gueinzius K et al (2003) Heterozygous toll-like receptor 4 polymorphism does not influence lipopolysaccharide-induced cytokine release in human whole blood. J Infect Dis 188:938–943. doi:10.1086/378095

    Article  Google Scholar 

  49. Paulus SC, Hirschfeld AF, Victor RE et al (2007) Common human Toll-like receptor 4 polymorphisms—role in susceptibility to respiratory syncytial virus infection and functional immunological relevance. Clin Immunol 123:252–277

    Article  PubMed  CAS  Google Scholar 

  50. Medvedev AE, Sabroe I, Hasday JD et al (2006) Tolerance to microbial TLR ligands: molecular mechanisms and relevance to disease. J Endotoxin Res 12:133–150. doi:10.1179/096805106X102255

    Article  PubMed  CAS  Google Scholar 

  51. Kobayashi K, Hernandez LD, Galán JE et al (2002) IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 110:191–202. doi:10.1016/S0092-8674(02)00827-9

    Article  PubMed  CAS  Google Scholar 

  52. Viboud GI, Bliska JB (2005) Yersinia outer proteins: role in modulation of host cell signaling responses and pathogenesis. Annu Rev Microbiol 59:69–89. doi:10.1146/annurev.micro.59.030804.121320

    Article  PubMed  CAS  Google Scholar 

  53. Cirl C, Wieser A, Yadav M et al (2008) Subversion of Toll-like receptor signaling by a unique family of bacterial Toll/interleukin-1 receptor domain-containing proteins. Nat Med 14:399–406. doi:10.1038/nm1734

    Article  PubMed  CAS  Google Scholar 

  54. Bochud PY, Hawn TR, Siddiqui MR et al (2008) Toll-like receptor 2 (TLR2) polymorphisms are associated with reversal reaction in leprosy. J Infect Dis 197:253–261. doi:10.1086/524688

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Swiss National Science Foundation (81LA-65462 to PYB), the Swiss Foundation for Medical-Biological Grants (1121 to PYB), the Leenaards Foundation (to PYB) and the National Institute of Health (AI25032 to AA, AI22616 and AI 54361 to GK). The AMFES project in Ethiopia was funded by the International Federation of Anti-Leprosy Associations (ILEP) Members through Netherlands Leprosy Relief (NLR). We thank Sarah Li for technical assistance with genotyping and Abraham Aseffa for his help and advice in bringing the manuscript to press.

The authors have no conflict of interest in the present manuscript.

Author information

Author notes

  1. P.-Y. Bochud

    Present address: Service of Infectious Diseases, Department of Medicine, Institute of Microbiology, University Hospital and University of Lausanne, 1011, Lausanne, Switzerland

  2. M. R. Siddiqui

    Present address: Centre for Infections, Health Protection Agency, London, UK

  3. P. Saunderson

    Present address: American Leprosy Missions, Greenville, SC, USA

  4. S. Britton

    Present address: Department of Medicine, Karolinska Institute, Stockholm, Sweden

  5. A. Tadesse Argaw

    Present address: Mount Sinai School of Medicine, New York, NY, USA

Authors and Affiliations

  1. Institute for Systems Biology, Seattle, WA, USA

    P.-Y. Bochud, A. Aderem, M. Janer & T. R. Hawn

  2. Department of Medicine, University of Washington, Seattle, WA, USA

    A. Aderem & T. R. Hawn

  3. Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute Center at the University of Medicine and Dentistry of New Jersey, Newark, NJ, USA

    D. Sinsimer, M. R. Siddiqui & G. Kaplan

  4. All Africa Leprosy Rehabilitation and Training, Addis Ababa, Ethiopia

    P. Saunderson

  5. Armauer Hansen Research Institute, Addis Ababa, Ethiopia

    S. Britton, I. Abraham & A. Tadesse Argaw

  6. Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA

    D. Sinsimer

Authors
  1. P.-Y. Bochud
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Sinsimer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Aderem
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. R. Siddiqui
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. Saunderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S. Britton
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. I. Abraham
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A. Tadesse Argaw
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M. Janer
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. T. R. Hawn
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. G. Kaplan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P.-Y. Bochud.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bochud, PY., Sinsimer, D., Aderem, A. et al. Polymorphisms in Toll-like receptor 4 (TLR4) are associated with protection against leprosy. Eur J Clin Microbiol Infect Dis 28, 1055–1065 (2009). https://doi.org/10.1007/s10096-009-0746-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10096-009-0746-0

Keywords

Search

Navigation