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pyrin蛋白的古地中海热突变帮助个体抵抗鼠疫杆菌感染
2020-06-30 20:43

2020年6月29日出版的《自然-免疫学》杂志在线发表了美国国家人类基因组研究所Jae Jin Chae和Daniel L. Kastner团队的最新成果。他们在人类pyrin中发现了古代地中海热突变以抵抗鼠疫杆菌。

通过对2313名土耳其人进行检测,研究人员发现了家族性地中海热(FMF)相关突变的扩展单倍型纯合侧枝,这表明在进化上对FMF相关突变的正向选择。两种致病性pyrin变体在1800年前就已独立出现。与人野生型pyrin相比,突变pyrin与鼠疫杆菌毒力因子YopM的相互作用不如野生型,因此减弱了由YopM诱导的白细胞介素1β的抑制作用。

相对于健康人,具有纯合或复合杂合突变的FMF患者以及无症状杂合携带者的白细胞释放更多IL-1β,特别是针对鼠疫杆菌感染。鼠疫杆菌感染时,与野生型敲入小鼠相比,MefvM680I / M680I FMF敲入小鼠的存活率表现出IL-1依赖性。因此,地中海人群中FMF突变的正向选择赋予了其对鼠疫杆菌增强的抗性。

研究人员表示,FMF是由MEFV的纯合或复合杂合功能获得突变引起的自身炎症性疾病,MEFV编码炎性蛋白pyrin。在多个地中海人群中,多样MEFV突变的杂合携带者出现频率很高,这表明它们具有选择性优势。

附:英文原文

Title: Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis

Author: Yong Hwan Park, Elaine F. Remmers, Wonyong Lee, Amanda K. Ombrello, Lawton K. Chung, Zhao Shilei, Deborah L. Stone, Maya I. Ivanov, Nicole A. Loeven, Karyl S. Barron, Patrycja Hoffmann, Michele Nehrebecky, Yeliz Z. Akkaya-Ulum, Erdal Sag, Banu Balci-Peynircioglu, Ivona Aksentijevich, Ahmet Gl, Charles N. Rotimi, Hua Chen, James B. Bliska, Seza Ozen, Daniel L. Kastner, Daniel Shriner, Jae Jin Chae

Issue&Volume: 2020-06-29

Abstract: Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by homozygous or compound heterozygous gain-of-function mutations in MEFV, which encodes pyrin, an inflammasome protein. Heterozygous carrier frequencies for multiple MEFV mutations are high in several Mediterranean populations, suggesting that they confer selective advantage. Among 2,313 Turkish people, we found extended haplotype homozygosity flanking FMF-associated mutations, indicating evolutionarily recent positive selection of FMF-associated mutations. Two pathogenic pyrin variants independently arose >1,800 years ago. Mutant pyrin interacts less avidly with Yersinia pestis virulence factor YopM than with wild-type human pyrin, thereby attenuating YopM-induced interleukin (IL)-1β suppression. Relative to healthy controls, leukocytes from patients with FMF harboring homozygous or compound heterozygous mutations and from asymptomatic heterozygous carriers released heightened IL-1β specifically in response to Y.pestis. Y.pestis-infected MefvM680I/M680I FMF knock-in mice exhibited IL-1-dependent increased survival relative to wild-type knock-in mice. Thus, FMF mutations that were positively selected in Mediterranean populations confer heightened resistance to Y.pestis.

DOI: 10.1038/s41590-020-0705-6

Source: https://www.nature.com/articles/s41590-020-0705-6

Nature Immunology:《自然—免疫学》,创刊于2000年。隶属于施普林格·自然出版集团,最新IF:23.53
官方网址:https://www.nature.com/ni/
投稿链接:https://mts-ni.nature.com/cgi-bin/main.plex


本期文章:《自然—免疫学》:Online/在线发表

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