The cyanobacterial saxitoxin exacerbates neural cell death and brain malformations induced by Zika virus
The cyanobacterial saxitoxin exacerbates neural cell death and brain malformations induced by Zika virus
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DOI：
10.1371/journal.pntd.0008060
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发表时间：
2020-03-01
影响因子：
3.8
通讯作者：
Rehen, Stevens K.
中科院分区：
文献类型：
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作者：
Pedrosa, Carolina da S. G.;Souza, Leticia R. Q.;Rehen, Stevens K.
蓝藻在饮用水水库中不受控制的蔓延已成为世界范围内严重的公共卫生问题的原因。产毒蓝藻繁殖通常发生在干旱期间在巴西东北（东北）地区。在2015-16年寨卡病毒（ZIKV）暴发期间，巴西东北地区出现了不成比例的小头症发病率。在这里，我们验证了一种假设，即蓝藻毒素（STX）可能作为ZIKV的共同侮辱。水质监测数据显示，2014-2018年东北地区蓝藻数量增加，STX数量增加。在体外，我们观察到STX暴露于zikv感染的脑类器官后，神经祖细胞死亡增加了一倍。在体内，妊娠期长期摄入STX可增强新生小鼠寨卡病毒衍生的大脑异常。我们的研究提供了新的见解，可以解释巴西各地区在CZS严重程度方面的差异。此外，这些数据强调了蓝藻细菌和蓝藻毒素淡水监测对未来虫媒病毒暴发的重要性。巴西东北（东北）地区通常经历干旱期，这有利于蓝藻繁殖，能够产生对人类和动物健康有影响的神经毒素。巴西历史上最严重的干旱发生在2012年至2016年。巧合的是，与寨卡病毒（ZIKV）暴发相关的小头畸形发病率最高的年份发生在巴西东北部地区。在这项工作中，我们验证了一种假设，即蛤蚌毒素（STX）是淡水蓝藻Raphidiopsis raciborskii在南美洲产生的一种神经毒素，可能导致了世界上最严重的先天性寨卡综合征（CZS）。质量监测显示，与巴西其他地区相比，东北地区人类饮用水供应中的蓝藻数量和STX发生率较高。在实验中，我们描述了STX在人类大脑类器官祖区诱导的神经细胞死亡数量增加了一倍，而在妊娠前和妊娠期间长期饮用被STX污染的水会导致感染zikv的免疫活性C57BL/6J小鼠后代的大脑异常。我们的数据表明，产石笋毒素的蓝藻在东北地区的水库中分布广泛，可能是巴西寨卡病毒感染的共同病原体。这些结果引起了公众对虫媒病毒在干旱和/或淡水蓝藻频繁繁殖地区暴发的后果的关注。
Author summaryThe uncontrolled spreading of cyanobacteria in drinking water reservoirs has been the cause of serious public health problems worldwide. Toxin-producing cyanobacterial blooms commonly occur during drought periods in the northeast (NE) region of Brazil. During Zika Virus (ZIKV) outbreak in 2015-16, Brazilian NE showed disproportionately higher microcephaly incidence. Here, we test the hypothesis that the cyanotoxin saxitoxin (STX) may act as a co-insult for ZIKV. Water quality surveillance data showed increased cyanobacteria population and higher STX amount in NE region during 2014-2018. In vitro, we observed that neural progenitor cell death was doubled after STX exposure to ZIKV-infected brain organoids. In vivo, chronic ingestion of STX during gestational period potentiated ZIKV-derived brain abnormalities in newborn mice. Our study provides new insights that may explain the discrepancies among Brazilian regions regarding CZS severity. Moreover, the data highlight the importance of cyanobacteria and cyanotoxin freshwater monitoring for future arbovirus outbreaks.The northeast (NE) region of Brazil commonly goes through drought periods, which favor cyanobacterial blooms, capable of producing neurotoxins with implications for human and animal health. The most severe dry spell in the history of Brazil occurred between 2012 and 2016. Coincidently, the highest incidence of microcephaly associated with the Zika virus (ZIKV) outbreak took place in the NE region of Brazil during the same years. In this work, we tested the hypothesis that saxitoxin (STX), a neurotoxin produced in South America by the freshwater cyanobacteria Raphidiopsis raciborskii, could have contributed to the most severe Congenital Zika Syndrome (CZS) profile described worldwide. Quality surveillance showed higher cyanobacteria amounts and STX occurrence in human drinking water supplies of NE compared to other regions of Brazil. Experimentally, we described that STX doubled the quantity of ZIKV-induced neural cell death in progenitor areas of human brain organoids, while the chronic ingestion of water contaminated with STX before and during gestation caused brain abnormalities in offspring of ZIKV-infected immunocompetent C57BL/6J mice. Our data indicate that saxitoxin-producing cyanobacteria is overspread in water reservoirs of the NE and might have acted as a co-insult to ZIKV infection in Brazil. These results raise a public health concern regarding the consequences of arbovirus outbreaks happening in areas with droughts and/or frequent freshwater cyanobacterial blooms.