The cyanobacterial saxitoxin exacerbates neural cell death and brain malformations induced by Zika virus

AbstractThe 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 was described 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 amount 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.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.