Functional and genetic evidence that the Mal/TIRAP allele variant 180L has been selected by providing protection against septic shock

doi:10.1073/pnas.0811273106

Functional and genetic evidence that the Mal/TIRAP allele variant 180L has been selected by providing protection against septic shock

^aDepartment of Internal Medicine and Nijmegen Institute for Infectious Inflammation and Immunity,
^fDepartment of Intensive Care Medicine, and
^rDepartment of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, P.O. Box 9101, Geert Grooteplein 8, 6500 HB, Nijmegen, The Netherlands;
^bDepartment of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, Barrio Sarriena s/n, 48940 Leioa, Bizkaia, Spain;
^cSchool of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland;
^dDepartment of Medical Microbiology Radboud University Nijmegen Medical Centre, 6525 GA, Nijmegen, The Netherlands;
^e4th Department of Internal Medicine, Attikon University Hospital, 1 Rimin Street, 124 62 Athens, Greece;
^gBarbara Davids Center for Childhood Diabetes, University of Colorado Health Science Center, Denver, CO 80262;
^hEijkman Institute for Molecular Biology, Diponegoro 69, Jakarta 10430, Indonesia;
ⁱDepartment of Anesthesiology, Iuliu Hatieganu University of Medicine and Pharmacy, P.O. Box 3400, 13 Emil Isaac Street, Cluj-Napoca, Romania;
^jInstitute of Tropical Medicine, Charité-University Medical Center, Spandauer Damm 130, D-14050 Berlin, Germany;
^kWenner-Gren Institute of Immunology, University of Stockholm, Svante Arrhenius väg 16-18, 106 91 Stockholm, Sweden;
^lDepartment of Surgery and Surgical Oncology, Robert-Rössle-Klinik, Charité-University Medical Center, Lindenberger Weg 80, 13125 Berlin, Germany;
^mDepartment of Epidemiology of Parasitic Disease, and
ⁿMalaria Research and Training Centre, Faculty of Medicine, University of Bamako, Campus de Badalabougou, BPE2528, Mali;
^oDepartment of Gastrointestinal Sciences, Christian Medical College Vellore 632004, Tamil Nadu, India;
^pDepartment of Medicine, Komfo Anokye Teaching Hospital, Kwame Nkrumah University of Science and Technology, P.O. Box 1934, Kumasi, Ghana;
^qInstitute for Microbiology and Hygiene, Charité-University Medical Center, Dorotheenstrasse 96, D-10117 Berlin, Germany; and
^sThe Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom

Edited by Shizuo Akira, Osaka University, Japan, and accepted by the Editorial Board May 1, 2009 (received for review November 11, 2008)

Abstract

Adequate responses by our innate immune system toward invading pathogens were of vital importance for surviving infections, especially before the antibiotic era. Recently, a polymorphism in Mal (Ser180Leu, TIRAP rs8177374), an important adaptor protein downstream of the Toll-like receptor (TLR) 2 and 4 pathways, has been described to provide protection against a broad range of infectious pathogens. We assessed the functional effects of this polymorphism in human experimental endotoxemia, and we demonstrate that individuals bearing the TIRAP 180L allele display an increased, innate immune response to TLR4 and TLR2 ligands, but not to TLR9 stimulation. This phenotype has been related to an increased resistance to infection. However, an overshoot in the release of proinflammatory cytokines by TIRAP 180L homozygous individuals suggests a scenario of balanced evolution. We have also investigated the worldwide distribution of the Ser180Leu polymorphism in 14 populations around the globe to correlate the genetic makeup of TIRAP with the local infectious pressures. Based on the immunological, clinical, and genetic data, we propose that this mutation might have been selected in West Eurasia during the early settlement of this region after the out-of-Africa migration of modern Homo sapiens. This combination of functional and genetic data provides unique insights to our understanding of the pathogenesis of sepsis.

Footnotes

¹To whom correspondence should be addressed. E-mail: m.netea{at}aig.umcn.nl
Author contributions: B.F., B.P.R., P.P., J.W.M.v.d.M., and M.G.N. designed research; B.F., S.A., K.B., M.B.B.M., E.J.G.-B., B.P.R., M.M., N.I., B.M., A.D., and O.D. performed research; S.A., K.B., M.B.B.M., E.J.G.-B., M.M., P.R.F., N.I., D.S., T.C., F.P.M., M.T.-B., O.K., B.M., A.D., O.D., S.S., G.B.-A., R.v.C., L.H., D.-Y.O., R.R.S., L.A.B.J., C.d.l.R., R.S., J.P.H.D., B.-J.K., A.J.A.M.v.d.V., A.V.H., and L.A.J.O. contributed new reagents/analytic tools; B.F., S.A., K.B., M.B.B.M., E.J.G.-B., and M.G.N. analyzed data; and B.F., S.A., and M.G.N. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. S.A. is a guest editor invited by the Editorial Board.