The Brazilian Zika virus strain causes birth defects in experimental models.
The Brazilian Zika virus strain causes birth defects in experimental models.
复制标题
DOI：
10.1038/nature18296
复制
发表时间：
2016-06-09
期刊：
影响因子：
64.8
通讯作者：
Beltrão-Braga PC
中科院分区：
文献类型：
--
作者：
Cugola FR;Fernandes IR;Russo FB;Freitas BC;Dias JL;Guimarães KP;Benazzato C;Almeida N;Pignatari GC;Romero S;Polonio CM;Cunha I;Freitas CL;Brandão WN;Rossato C;Andrade DG;Faria Dde P;Garcez AT;Buchpigel CA;Braconi CT;Mendes E;Sall AA;Zanotto PM;Peron JP;Muotri AR;Beltrão-Braga PC
寨卡病毒（ZIKV）是一种虫媒病毒，属于黄病毒属（黄病毒科），于1947年在乌干达对前哨恒河猴进行血液分析后首次发现。直到20世纪，该病毒的非洲和亚洲谱系都没有在人类中引起有意义的感染。然而，2007年，以埃及伊蚊为媒介的寨卡病毒在密克罗尼西亚的雅浦岛引起了第一次值得注意的流行病。患者出现发热、皮疹、关节痛和结膜炎。2013年至2015年，该病毒的亚洲谱系在新喀里多尼亚和法属波利尼西亚造成了进一步的大规模疫情。2013年，寨卡病毒到达巴西，随后传播到南美洲和中美洲的其他国家。在巴西，这种病毒与先天性畸形有关，包括小头畸形和其他严重的神经系统疾病，如格林-巴罗综合征。尽管有临床证据，但表明巴西寨卡病毒（ZIKVBR）毒株导致出生缺陷的直接实验证据仍然缺失。在这里，我们证明ZIKVBR感染胎儿，引起子宫内生长受限（IUGR），包括小鼠小头畸形的迹象。此外，该病毒感染人类皮质祖细胞，导致细胞死亡增加。最后，我们观察到人类大脑类器官的感染导致增殖区减少和皮层破坏。这些结果表明，ZIKVBR穿过胎盘，以皮质祖细胞为靶点，通过细胞凋亡和自噬诱导细胞死亡，损害神经发育，从而导致小头畸形。我们的数据进一步证明，越来越多的证据将寨卡病毒流行与数量惊人的先天性脑畸形病例联系起来。我们的模型可以用来确定治疗方法的效率，以抵消ZIKVBR对人类神经发育的有害影响。
Zika virus (ZIKV) is an arbovirus belonging to the genus Flavivirus (Family Flaviviridae) and was first described in 1947 in Uganda following blood analyses of sentinel Rhesus monkeys. Until the 20th century, the African and Asian lineages of the virus did not cause meaningful infections in humans. However, in 2007, vectored by Aedes aegypti mosquitoes, ZIKV caused the first noteworthy epidemic on the island of Yap in Micronesia. Patients experienced fever, skin rash, arthralgia and conjunctivitis. From 2013 to 2015, the Asian lineage of the virus caused further massive outbreaks in New Caledonia and French Polynesia. In 2013, ZIKV reached Brazil, later spreading to other countries in South and Central America. In Brazil, the virus has been linked to congenital malformations, including microcephaly and other severe neurological diseases, such as Guillain-Barré syndrome. Despite clinical evidence, direct experimental proof showing that the Brazilian ZIKV (ZIKVBR) strain causes birth defects remains missing. Here we demonstrate that the ZIKVBR infects fetuses, causing intra-uterine growth restriction (IUGR), including signs of microcephaly in mice. Moreover, the virus infects human cortical progenitor cells, leading to an increase in cell death. Finally, we observed that the infection of human brain organoids resulted in a reduction of proliferative zones and disrupted cortical layers. These results indicate that ZIKVBR crosses the placenta and causes microcephaly by targeting cortical progenitor cells, inducing cell death by apoptosis and autophagy, impairing neurodevelopment. Our data reinforce the growing body of evidence linking the ZIKVBR outbreak to the alarming number of cases of congenital brain malformations. Our model can be used to determine the efficiency of therapeutic approaches to counteracting the harmful impact of ZIKVBR in human neurodevelopment.