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

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.

• Authors: Bart Ferwerda, Santos Alonso, Kathy Banahan, Matthew B B McCall, Evangelos J Giamarellos-Bourboulis, Bart P Ramakers, Maria Mouktaroudi, Pamela R Fain, Neskuts Izagirre, Din Syafruddin, Tudor Cristea, Frank P Mockenhaupt, Marita Troye-Blomberg, Oliver Kumpf, Boubacar Maiga, Amagana Dolo, Ogobara Doumbo, Santhosh Sundaresan, George Bedu-Addo, Reinout van Crevel, Lutz Hamann, Djin-Ye Oh, Ralf R Schumann, Leo A B Joosten, Concepcion de la Rúa, Robert Sauerwein, Joost P H Drenth, Bart-Jan Kullberg, André J A M van der Ven, Adrian V Hill, Peter Pickkers, Jos W M van der Meer, Luke A J O'Neill, Mihai G Netea
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 25 Pg. 10272-7 (Jun 23 2009) ISSN: 1091-6490 [Electronic] United States
• PMID: 19509334 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Membrane Glycoproteins
• Receptors, Interleukin-1
• TIRAP protein, human
• Serine
• Leucine

Topics

• Alleles
• Endotoxemia (genetics, immunology)
• Humans
• Immunity, Innate (genetics)
• Leucine (genetics)
• Membrane Glycoproteins (genetics, physiology)
• Polymorphism, Genetic
• Receptors, Interleukin-1 (genetics, physiology)
• Selection, Genetic
• Serine (genetics)
• Shock, Septic (genetics, immunology)