A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis

Article metrics

Abstract

Toll-like receptors (TLRs) and members of their signaling pathway are important in the initiation of the innate immune response to a wide variety of pathogens1,2,3. The adaptor protein Mal (also known as TIRAP), encoded by TIRAP (MIM 606252), mediates downstream signaling of TLR2 and TLR4 (refs. 46). We report a case-control study of 6,106 individuals from the UK, Vietnam and several African countries with invasive pneumococcal disease, bacteremia, malaria and tuberculosis. We genotyped 33 SNPs, including rs8177374, which encodes a leucine substitution at Ser180 of Mal. We found that heterozygous carriage of this variant associated independently with all four infectious diseases in the different study populations. Combining the study groups, we found substantial support for a protective effect of S180L heterozygosity against these infectious diseases (N = 6,106; overall P = 9.6 × 10−8). We found that the Mal S180L variant attenuated TLR2 signal transduction.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Functional analysis of Mal Ser180 and Mal Leu180.
Figure 2: Molecular models of wild-type and mutant Mal.
Figure 3: HEK293 cells (1 × 106) were transfected with 3 μg of Flag-tagged TLR2, hemagglutinin (HA)-Mal or AU1-tagged MyD88.

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. 1

    Akira, S. & Takeda, K. Toll-like receptor signalling. Nat. Rev. Immunol. 4, 499–511 (2004).

  2. 2

    Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003).

  3. 3

    Akira, S., Takeda, K. & Kaisho, T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat. Immunol. 2, 675–680 (2001).

  4. 4

    Fitzgerald, K.A. et al. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 413, 78–83 (2001).

  5. 5

    Yamamoto, M. et al. Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420, 324–329 (2002).

  6. 6

    Horng, T., Barton, G.M., Flavell, R.A. & Medzhitov, R. The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature 420, 329–333 (2002).

  7. 7

    Poltorak, A. et al. Defective LPS signalling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).

  8. 8

    Hoshino, K. et al. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J. Immunol. 162, 3749–3752 (1999).

  9. 9

    Shimazu, R. et al. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J. Exp. Med. 189, 1777–1782 (1999).

  10. 10

    Krishnegowda, G. et al. Induction of proinflammatory responses in macrophages by the glycosylphosphatidylinositols of Plasmodium falciparum: cell signalling receptors, glycosylphosphatidylinositol (GPI) structural requirement, and regulation of GPI activity. J. Biol. Chem. 280, 8606–8616 (2005).

  11. 11

    Dunne, A., Ejdeback, M., Ludidi, P.L., O'Neill, L.A. & Gay, N.J. Structural complementarity of Toll/interleukin-1 receptor domains in Toll-like receptors and the adaptors TIRAP and MyD88. J. Biol. Chem. 278, 41443–41451 (2003).

  12. 12

    Thoma-Uszynski, S. et al. Induction of direct antimicrobial activity through mammalian toll-like receptors. Science 291, 1544–1547 (2001).

  13. 13

    Malley, R. et al. Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection. Proc. Natl. Acad. Sci. USA 100, 1966–1971 (2003).

  14. 14

    Aitman, T.J. et al. Malaria susceptibility and CD36 mutation. Nature 405, 1015–1016 (2000).

  15. 15

    Hoebe, K. et al. CD36 is a sensor of diacylglycerides. Nature 433, 523–527 (2005).

  16. 16

    Miller, L.H., Baruch, D.I., Marsh, K. & Doumbo, O.K. The pathogenic basis of malaria. Nature 415, 673–679 (2002).

  17. 17

    Annane, D., Bellissant, E. & Cavaillon, J.M. Septic shock. Lancet 365, 63–78 (2005).

  18. 18

    Cundell, D.R., Gerard, N.P., Gerard, C., Idanpaan-Heikkila, I. & Tuomanen, E.I. Streptococcus pneumoniae anchor to activated human cells by the receptor for platelet-activating factor. Nature 377, 435–438 (1995).

  19. 19

    Dean, M., Carrington, M. & O'Brien, S.J. Balanced polymorphism selected by genetic versus infectious human disease. Annu. Rev. Genomics Hum. Genet. 3, 263–292 (2002).

  20. 20

    Mead, S. et al. Balancing selection at the prion protein gene consistent with prehistoric kurulike epidemics. Science 300, 640–643 (2003).

  21. 21

    Carrington, M. et al. HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage. Science 283, 1748–1752 (1999).

  22. 22

    Picard, C. et al. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299, 2076–2079 (2003).

  23. 23

    Doffinger, R. et al. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Nat. Genet. 27, 277–285 (2001).

  24. 24

    Clatworthy, M.R. & Smith, K.G. FcgammaRIIb balances efficient pathogen clearance and the cytokine-mediated consequences of sepsis. J. Exp. Med. 199, 717–723 (2004).

  25. 25

    Jurinke, C., van den Boom, D., Cantor, C.R. & Koster, H. The use of MassARRAY technology for high throughput genotyping. Adv. Biochem. Eng. Biotechnol. 77, 57–74 (2002).

  26. 26

    Altshuler, D. et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat. Genet. 26, 76–80 (2000).

  27. 27

    Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

  28. 28

    Clayton, D. A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. Am. J. Hum. Genet. 65, 1170 (1999).

Download references

Acknowledgements

The authors would like to thank all the participants and the many investigators involved in the original case-control studies in Algeria, the Gambia, Guinea-Bissau, Republic of Guinea, Kenya, Vietnam and the UK for their contributions. This paper was published with the permission of the director of the Kenya Medical Research Institute (KEMRI). We thank K. Fitzgerald (University of Massachusetts) for the gift of the Mal-deficient fibroblasts. This work was funded by the Wellcome Trust, Science Foundation Ireland, Irish Health Research Board and the Agency for Science, Technology and Research (A-STAR), Singapore. C.C.K. and R.T.G. are scholars of A-STAR, and are members of the Bachelor of Medicine and Surgery (MBBS)-PhD program, Faculty of Medicine, National University of Singapore. F.O.V. is supported by the EU FP6 GenoSept grant and the UK ORS Scheme. S.J.C. is a Wellcome Trust Clinical Research Fellow; A.V.S.H. is a Wellcome Trust Principal Fellow.

Author information

C.C.K., S.J.C. and F.O.V. performed genotyping and wrote the article. A.D. and C.M. carried out functional experiments on Mal. O.K. and A.K. performed the modeling analysis on Mal. E.Y.L., A.J.F., A.J.W., C.A., S.S., C.E.M., K.K., S.J.C. and R.T.G. contributed to the experimental design of the genetic studies. C.L., A.S., P.A., O.Y.S., J.S., G.S., N.P., T.N.W., K.M., R.J.O.D., D.P.K., N.P.D., D.Y., D.W.C., K.M. and J.A.B. contributed to the design and collection of the case-control studies. All authors critically reviewed the manuscript. L.A.J.O'N. & A.V.S.H. led the functional and genetic efforts, respectively, and contributed equally to this work.

Correspondence to Luke A J O'Neill or Adrian V S Hill.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Genomic organization and linkage disequilibrium of TIRAP and surrounding region. (PDF 693 kb)

Supplementary Table 1

Allele frequency and P value for each polymorphism in TIRAP and the surrounding region genotyped in the UK IPD and Gambian malaria case-control studies. (PDF 31 kb)

Supplementary Table 2

Genotype frequencies for each polymorphism in TIRAP and the surrounding region genotyped in the UK IPD and Gambian malaria case-control studies. (PDF 87 kb)

Supplementary Table 3

Primer sequences. (PDF 43 kb)

Supplementary Methods (PDF 87 kb)

Supplementary Note (PDF 10 kb)

Rights and permissions

Reprints and Permissions

About this article

Further reading