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

被引：74

作者：

Ferwerda, Bart ^{[1
,2
]}

Alonso, Santos ^{[5
]}

Banahan, Kathy ^{[6
]}

McCall, Matthew B. B. ^{[1
,2
,7
]}

Giamarellos-Bourboulis, Evangelos J. ^{[8
]}

Ramakers, Bart P. ^{[3
]}

Mouktaroudi, Maria ^{[8
]}

Fain, Pamela R. ^{[9
]}

Izagirre, Neskuts ^{[5
]}

Syafruddin, Din ^{[10
]}

Cristea, Tudor ^{[11
]}

Mockenhaupt, Frank P. ^{[12
]}

Troye-Blomberg, Marita ^{[13
]}

Kumpf, Oliver ^{[14
]}

Maiga, Boubacar ^{[15
]}

Dolo, Amagana ^{[16
]}

Doumbo, Ogobara ^{[16
]}

Sundaresan, Santhosh ^{[17
]}

Bedu-Addo, George ^{[18
]}

van Crevel, Reinout ^{[1
,2
]}

Hamann, Lutz ^{[12
,19
]}

Oh, Djin-Ye ^{[19
]}

Schumann, Ralf R. ^{[19
]}

Joosten, Leo A. B. ^{[1
,2
]}

de la Rua, Concepcion ^{[5
]}

Sauerwein, Robert ^{[7
]}

Drenth, Joost P. H. ^{[4
]}

Kullberg, Bart-Jan ^{[1
,2
]}

van der Ven, Andre J. A. M. ^{[1
,2
]}

Hills, Adrian V. ^{[20
]}

Pickkers, Peter ^{[3
]}

van der Meer, Jos W. M. ^{[1
,2
]}

O'Neill, Luke A. J. ^{[6
]}

Netea, Mihai G. ^{[1
,2
]}

机构：

[1] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6500 HB Nijmegen, Netherlands

[2] Radboud Univ Nijmegen, Med Ctr, Nijmegen Inst Infect Inflammat & Immun, NL-6500 HB Nijmegen, Netherlands

[3] Radboud Univ Nijmegen, Med Ctr, Dept Intens Care Med, NL-6500 HB Nijmegen, Netherlands

[4] Radboud Univ Nijmegen, Med Ctr, Dept Gastroenterol & Hepatol, NL-6500 HB Nijmegen, Netherlands

[5] Univ Basque Country, Dept Genet Phys Anthropol & Anim Physiol, Leioa 48940, Bizkaia, Spain

[6] Trinity Coll Dublin, Sch Biochem & Immunol, Dublin 2, Ireland

[7] Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, NL-6525 GA Nijmegen, Netherlands

[8] Attikon Univ Hosp, Dept Internal Med 4, Athens, Greece

[9] Univ Colorado, Hlth Sci Ctr, Barbara Davis Ctr Childhood Diabet, Denver, CO 80262 USA

[10] Eijkman Inst Mol Biol, Jakarta 10430, Indonesia

[11] Iuliu Hatieganu Univ Med & Pharm, Dept Anesthesiol, Cluj Napoca, Romania

[12] Charite Univ Med Berlin, Med Ctr, Inst Trop Med, D-14050 Berlin, Germany

[13] Univ Stockholm, Wenner Gren Inst Immunol, S-10691 Stockholm, Sweden

[14] Charite Univ Med Berlin, Med Ctr, Robert Rossle Klin, Dept Surg & Surg Oncol, D-13125 Berlin, Germany

[15] Univ Bamako, Fac Med, Dept Epidemiol Parasit Dis, Bamako, Mali

[16] Univ Bamako, Fac Med, Malaria Res & Training Ctr, Bamako, Mali

[17] Christian Med Coll Vellore, Dept Gastrointestinal Sci, Vellore 632004, Tamil Nadu, India

[18] Kwame Nkrumah Univ Sci & Technol, Dept Med, Komfo Anokye Teaching Hosp, Kumasi, Ghana

[19] Charite Univ Med Berlin, Med Ctr, Inst Microbiol & Hyg, D-10117 Berlin, Germany

[20] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 25期

基金：

爱尔兰科学基金会;

关键词：

Innate immunity; TLR4; TLR2; evolution; cytokines; HUMAN GENOME; SEQUENCE VARIATION; NATURAL-SELECTION; SEPSIS; TLR4; POLYMORPHISMS;

D O I：

10.1073/pnas.0811273106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：10272 / 10277

页数：6

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