Pathogenicity Determinants of the Human Malaria Parasite Plasmodium falciparum Have Ancient Origins.
Pathogenicity Determinants of the Human Malaria Parasite Plasmodium falciparum Have Ancient Origins.
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DOI：
10.1128/msphere.00348-16
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发表时间：
2017-01
期刊：
影响因子：
4.8
通讯作者：
Smith JD
中科院分区：
文献类型：
--
作者：
Brazier AJ;Avril M;Bernabeu M;Benjamin M;Smith JD
恶性疟原虫感染的红细胞在微循环中的细胞粘附是一个主要的毒力决定因素。恶性疟原虫是寄生虫的一个亚属的后代，也感染黑猩猩和大猩猩，并表现出严格的宿主物种特异性。尽管它们与恶性疟原虫具有高度的遗传相似性，但目前尚不清楚猿类寄生虫是否编码与恶性疟原虫相似的粘附特性或在其天然宿主中具有同样的毒性。因此，目前还不清楚恶性疟原虫中的毒力粘附性状何时出现以及它们在寄生虫种群中存在了多久。也不知道细胞粘附相互作用是否对跨物种传播构成障碍。我们表明，寄生虫领域从黑猩猩疟疾寄生虫P. reichenowi结合人类受体的特异性类似的恶性疟原虫。我们的研究结果表明，与轻度和重度疟疾相关的寄生虫粘附性状的起源比以前认识到的要早得多，并对人类主要病原体的毒力进化具有重要意义。恶性疟原虫是最致命的人类疟疾寄生虫，是Laverania亚属的一员，也感染非洲大猿。恶性疟原虫的毒力与感染红细胞在微血管中的细胞粘附有关，但对恶性疟原虫粘附特性的起源知之甚少。为了研究恶性疟原虫细胞粘附致病性决定簇的进化历史，我们研究了黑猩猩疟原虫赖氏疟原虫的粘附结构域。我们证明，赖氏疟原虫变种基因库编码富含半胱氨酸的域间区域（CIDR）域结合人CD 36和内皮蛋白C受体（EPCR）具有相同的亲和力水平和在结合位点类似的恶性疟原虫。此外，P. reichenowi结构域干扰活化蛋白C-EPCR途径对内皮细胞的保护功能，这是人类的推定毒力特征。这些发现为恶性疟原虫的两个关键细胞粘附特性的古老进化起源提供了证据，这两个特性有助于人类感染和致病性。恶性疟原虫感染的红细胞在微循环中的细胞粘附是一个主要的毒力决定因素。恶性疟原虫是寄生虫的一个亚属的后代，也感染黑猩猩和大猩猩，并表现出严格的宿主物种特异性。尽管它们与恶性疟原虫具有高度的遗传相似性，但目前尚不清楚猿类寄生虫是否编码与恶性疟原虫相似的粘附特性或在其天然宿主中具有同样的毒性。因此，目前还不清楚恶性疟原虫中的毒力粘附性状何时出现以及它们在寄生虫种群中存在了多久。也不知道细胞粘附相互作用是否对跨物种传播构成障碍。我们表明，寄生虫领域从黑猩猩疟疾寄生虫P. reichenowi结合人类受体的特异性类似的恶性疟原虫。我们的研究结果表明，与轻度和重度疟疾相关的寄生虫粘附性状的起源比以前认识到的要早得多，并对人类主要病原体的毒力进化具有重要意义。
Cytoadhesion of P. falciparum-infected erythrocytes in the microcirculation is a major virulence determinant. P. falciparum is descended from a subgenus of parasites that also infect chimpanzees and gorillas and exhibits strict host species specificity. Despite their high genetic similarity to P. falciparum, it is unknown whether ape parasites encode adhesion properties similar to those of P. falciparum or are as virulent in their natural hosts. Consequently, it has been unclear when virulent adhesion traits arose in P. falciparum and how long they have been present in the parasite population. It is also unknown whether cytoadhesive interactions pose a barrier to cross-species transmission. We show that parasite domains from the chimpanzee malaria parasite P. reichenowi bind human receptors with specificity similar to that of P. falciparum. Our findings suggest that parasite adhesion traits associated with both mild and severe malaria have much earlier origins than previously appreciated and have important implications for virulence evolution in a major human pathogen. Plasmodium falciparum, the most deadly of the human malaria parasites, is a member of the Laverania subgenus that also infects African Great Apes. The virulence of P. falciparum is related to cytoadhesion of infected erythrocytes in microvasculature, but the origin of dangerous parasite adhesion traits is poorly understood. To investigate the evolutionary history of the P. falciparum cytoadhesion pathogenicity determinant, we studied adhesion domains from the chimpanzee malaria parasite P. reichenowi. We demonstrate that the P. reichenowi var gene repertoire encodes cysteine-rich interdomain region (CIDR) domains which bind human CD36 and endothelial protein C receptor (EPCR) with the same levels of affinity and at binding sites similar to those bound by P. falciparum. Moreover, P. reichenowi domains interfere with the protective function of the activated protein C-EPCR pathway on endothelial cells, a presumptive virulence trait in humans. These findings provide evidence for ancient evolutionary origins of two key cytoadhesion properties of P. falciparum that contribute to human infection and pathogenicity. IMPORTANCE Cytoadhesion of P. falciparum-infected erythrocytes in the microcirculation is a major virulence determinant. P. falciparum is descended from a subgenus of parasites that also infect chimpanzees and gorillas and exhibits strict host species specificity. Despite their high genetic similarity to P. falciparum, it is unknown whether ape parasites encode adhesion properties similar to those of P. falciparum or are as virulent in their natural hosts. Consequently, it has been unclear when virulent adhesion traits arose in P. falciparum and how long they have been present in the parasite population. It is also unknown whether cytoadhesive interactions pose a barrier to cross-species transmission. We show that parasite domains from the chimpanzee malaria parasite P. reichenowi bind human receptors with specificity similar to that of P. falciparum. Our findings suggest that parasite adhesion traits associated with both mild and severe malaria have much earlier origins than previously appreciated and have important implications for virulence evolution in a major human pathogen.