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

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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.

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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.

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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.

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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)

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