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A Zika virus envelope mutation preceding the 2015 epidemic enhances virulence and fitness for transmission.
Proceedings of the National Academy of Sciences of the United States of America ( IF 11.1 ) Pub Date : 2020-08-18 , DOI: 10.1073/pnas.2005722117
Chao Shan 1, 2 , Hongjie Xia 3 , Sherry L Haller 4, 5, 6 , Sasha R Azar 4, 5, 6 , Yang Liu 3 , Jianying Liu 4, 5 , Antonio E Muruato 4 , Rubing Chen 4, 5, 6, 7 , Shannan L Rossi 4, 5, 7 , Maki Wakamiya 3 , Nikos Vasilakis 5, 7, 8, 9, 10 , Rongjuan Pei 2 , Camila R Fontes-Garfias 3 , Sanjay Kumar Singh 11 , Xuping Xie 3 , Scott C Weaver 5, 6, 12, 13, 14 , Pei-Yong Shi 1, 5, 6, 13, 14
Affiliation  

Arboviruses maintain high mutation rates due to lack of proofreading ability of their viral polymerases, in some cases facilitating adaptive evolution and emergence. Here we show that, just before its 2013 spread to the Americas, Zika virus (ZIKV) underwent an envelope protein V473M substitution (E-V473M) that increased neurovirulence, maternal-to-fetal transmission, and viremia to facilitate urban transmission. A preepidemic Asian ZIKV strain (FSS13025 isolated in Cambodia in 2010) engineered with the V473M substitution significantly increased neurovirulence in neonatal mice and produced higher viral loads in the placenta and fetal heads in pregnant mice. Conversely, an epidemic ZIKV strain (PRVABC59 isolated in Puerto Rico in 2015) engineered with the inverse M473V substitution reversed the pathogenic phenotypes. Although E-V473M did not affect oral infection of Aedes aegypti mosquitoes, competition experiments in cynomolgus macaques showed that this mutation increased its fitness for viremia generation, suggesting adaptive evolution for human viremia and hence transmission. Mechanistically, the V473M mutation, located at the second transmembrane helix of the E protein, enhances virion morphogenesis. Overall, our study revealed E-V473M as a critical determinant for enhanced ZIKV virulence, intrauterine transmission during pregnancy, and viremia to facilitate urban transmission.



中文翻译:

2015 年流行之前的寨卡病毒包膜突变增强了毒力和传播适应性。

由于缺乏病毒聚合酶的校对能力,虫媒病毒保持高突变率,在某些情况下促进适应性进化和出现。在这里,我们表明,就在 2013 年传播到美洲之前,寨卡病毒 (ZIKV) 经历了包膜蛋白 V473M 替代 (E-V473M),该替代增加了神经毒力、母婴传播和病毒血症,从而促进了城市传播。流行前的亚洲 ZIKV 毒株(2010 年在柬埔寨分离出的 FSS13025)用 V473M 替代基因工程改造,显着增加了新生小鼠的神经毒力,并在怀孕小鼠的胎盘和胎头中产生了更高的病毒载量。相反,一种流行的 ZIKV 毒株(2015 年在波多黎各分离出的 PRVABC59)通过反向 M473V 替代进行了工程改造,逆转了致病表型。埃及伊蚊、食蟹猴的竞争实验表明,这种突变增加了其对病毒血症产生的适应性,表明人类病毒血症的适应性进化以及传播。从机制上讲,位于 E 蛋白第二个跨膜螺旋的 V473M 突变增强了病毒颗粒的形态发生。总体而言,我们的研究表明 E-V473M 是增强 ZIKV 毒力、妊娠期间宫内传播和促进城市传播的病毒血症的关键决定因素。

更新日期:2020-08-19
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