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

Carolina da S. G. Pedrosa, Leticia R. Q. Souza, Caroline V. F. de Lima, Pitia F. Ledur, Karina Karmirian, Tiago A. Gomes, Jimena Barbeito-Andres, Marcelo do N. Costa, Luiza M. Higa, Maria Bellio, Flavio A. Lara, Amilcar Tanuri, Patricia P. Garcez, Arnaldo Prata-Barbosa, Fernanda Tovar-Moll, Renato J. R. Molica, View ORCID ProfileStevens K. Rehen
doi: https://doi.org/10.1101/755066
Carolina da S. G. Pedrosa
1D’Or Institute for Research and Education (IDOR), Rio de Janeiro, RJ, Brazil
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Leticia R. Q. Souza
1D’Or Institute for Research and Education (IDOR), Rio de Janeiro, RJ, Brazil
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Caroline V. F. de Lima
1D’Or Institute for Research and Education (IDOR), Rio de Janeiro, RJ, Brazil
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Pitia F. Ledur
1D’Or Institute for Research and Education (IDOR), Rio de Janeiro, RJ, Brazil
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Karina Karmirian
1D’Or Institute for Research and Education (IDOR), Rio de Janeiro, RJ, Brazil
2Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
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Tiago A. Gomes
3Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, RJ, Brazil
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Jimena Barbeito-Andres
2Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
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Marcelo do N. Costa
2Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
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Luiza M. Higa
4Department of Genetics, Institute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
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Maria Bellio
5Institute of Microbiology Paulo de Goes, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
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Flavio A. Lara
3Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, RJ, Brazil
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Amilcar Tanuri
4Department of Genetics, Institute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
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Patricia P. Garcez
2Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
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Arnaldo Prata-Barbosa
1D’Or Institute for Research and Education (IDOR), Rio de Janeiro, RJ, Brazil
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Fernanda Tovar-Moll
1D’Or Institute for Research and Education (IDOR), Rio de Janeiro, RJ, Brazil
2Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
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Renato J. R. Molica
6Academic Unit of Garanhuns, Federal Rural University of Pernambuco, Garanhuns, PE, Brazil
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Stevens K. Rehen
1D’Or Institute for Research and Education (IDOR), Rio de Janeiro, RJ, Brazil
2Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
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  • ORCID record for Stevens K. Rehen
  • For correspondence: srehen@lance-ufrj.org
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Abstract

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 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 summary The 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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted September 04, 2019.
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The cyanobacterial saxitoxin exacerbates neural cell death and brain malformations induced by Zika virus
Carolina da S. G. Pedrosa, Leticia R. Q. Souza, Caroline V. F. de Lima, Pitia F. Ledur, Karina Karmirian, Tiago A. Gomes, Jimena Barbeito-Andres, Marcelo do N. Costa, Luiza M. Higa, Maria Bellio, Flavio A. Lara, Amilcar Tanuri, Patricia P. Garcez, Arnaldo Prata-Barbosa, Fernanda Tovar-Moll, Renato J. R. Molica, Stevens K. Rehen
bioRxiv 755066; doi: https://doi.org/10.1101/755066
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The cyanobacterial saxitoxin exacerbates neural cell death and brain malformations induced by Zika virus
Carolina da S. G. Pedrosa, Leticia R. Q. Souza, Caroline V. F. de Lima, Pitia F. Ledur, Karina Karmirian, Tiago A. Gomes, Jimena Barbeito-Andres, Marcelo do N. Costa, Luiza M. Higa, Maria Bellio, Flavio A. Lara, Amilcar Tanuri, Patricia P. Garcez, Arnaldo Prata-Barbosa, Fernanda Tovar-Moll, Renato J. R. Molica, Stevens K. Rehen
bioRxiv 755066; doi: https://doi.org/10.1101/755066

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