The triumph of good over evil: protection by the sickle gene against malaria
The triumph of good over evil: protection by the sickle gene against malaria
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DOI：
10.1182/blood-2012-08-449397
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发表时间：
2013-01-03
期刊：
影响因子：
20.3
通讯作者：
Bunn, H. Franklin
中科院分区：
文献类型：
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作者：
Bunn, H. Franklin
镰状性状的恶性疟原虫耐药机制已经被积极研究了半个多世纪。本展望回顾了解决这一具有挑战性问题的进展，包括最近利用寄生虫基因组学和蛋白质组学的研究。被寄生的AS红细胞中Hb S聚合物的形成导致寄生虫生长发育受损，同时血液循环中的清除增强，毛细血管后深层血管床的沉积减少。镰状AS红细胞中活性氧的生成增强是地中海贫血和g6pd缺陷红细胞共有的一个发病特征，它会引发红细胞质膜的异常拓扑结构，并导致PfEMP-1（一种恶性疟原虫粘附蛋白，对内皮粘附至关重要）的表达减少和紊乱。小鼠Hb S模型通过抑制致病性CD8(+) T细胞和诱导血红素加氧酶-1，赋予宿主对伯氏疟原虫的耐受性。另一种明显独立的保护模式是在AS红细胞中选择性表达两种microRNA，这些microRNA整合到恶性疟原虫mrna中，抑制翻译和寄生虫生长。[血液。2013;121(1):20-25]
The mechanisms underlying Plasmodium falciparum resistance in persons with sickle trait have been under active investigation for more than a half century. This Perspective reviews progress in solving this challenging problem, including recent studies that have exploited the genomics and proteomics of the parasite. The formation of Hb S polymer in the parasitized AS RBC leads to impaired parasite growth and development along with enhanced clearance from the circulation and reduced deposition in deep post-capillary vascular beds. Enhanced generation of reactive oxygen species in sickled AS RBCs is a pathogenetic feature shared by parasitized thalassemic and G6PD-deficient RBCs, triggering abnormal topology of the RBC plasma membrane with decreased and disordered display of PfEMP-1, a P falciparum adhesion protein critical for endothelial adherence. A mouse model of Hb S confers host tolerance to P berghei, through inhibition of pathogenic CD8(+) T cells and induction of heme oxygenase-1. An additional and apparently independent mode of protection is provided by the selective expression in AS RBCs of 2 species of microRNA that integrate into P falciparum mRNAs and inhibit translation and parasite growth. (Blood. 2013; 121(1): 20-25)