Functional and genetic evidence that the Mal/TIRAP allele variant 180L has been selected by providing protection against septic shock
Functional and genetic evidence that the Mal/TIRAP allele variant 180L has been selected by providing protection against septic shock
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DOI：
10.1073/pnas.0811273106
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发表时间：
2009-06-23
影响因子：
11.1
通讯作者：
Netea, Mihai G.
中科院分区：
文献类型：
--
作者：
Ferwerda, Bart;Alonso, Santos;Netea, Mihai G.
我们的先天免疫系统对入侵病原体的充分反应对于感染的生存至关重要，特别是在抗生素时代之前。最近，Mal（Ser180Leu，TIRAP rs8177374）（Toll样受体（TLR）2和4途径下游的重要衔接蛋白）的多态性已被描述为提供针对广泛的感染性病原体的保护。我们评估了这种多态性在人类实验性内毒素血症中的功能效应，我们证明携带TIRAP 180 L等位基因的个体显示对TLR4和TLR2配体的先天性免疫应答增加，但对TLR9刺激没有。这种表型与对感染的抗性增加有关。然而，TIRAP 180L纯合子个体释放促炎细胞因子的过冲表明了平衡进化的情况。我们还调查了地球仪14个人群中Ser180 Leu多态性的全球分布，以将TIRAP的遗传组成与当地的感染压力相关联。基于免疫学、临床和遗传学数据，我们提出，这种突变可能是在现代智人从非洲迁移到该地区后的早期定居过程中在西欧亚大陆选择的。这种功能和遗传数据的结合为我们理解脓毒症的发病机制提供了独特的见解。
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.