Functional And Genetic Evidence That The Mal/TIRAP Allele Variant 180L Has Been Selected By Providing Protection Against Septic Shock

Here’s the abstract of a recent paper at PNAS, in which the authors propose that a mutation on the TIRAP gene amongst our earliest European ancestors may have enabled them to tweak their immune systems to the extent they were better equipped to fight illnesses such as malaria and tuberculosis.

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.

Although the paper is behind a paywall, its content and implications are discussed in this article, SNPwatch: Genetic Variation May Help Immune System Put Up Just The Right Amount Of Fight, over at The Spittoon.

In another article that discusses the innate immune system, Science Daily have this, Autoinflammatory Disease Model Reveals Role For Innate, Not Adaptive, Immunity.

Reference: Functional And Genetic Evidence That The Mal/TIRAP Allele Variant 180L Has Been Selected By Providing Protection Against Septic Shock

Bart Ferwerda,  Santos Alonso, Kathy Banahan et al

Published online before print June 9, 2009, doi: 10.1073/pnas.0811273106

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