Abstract
Infection of pregnant women by Zika virus (ZIKV) is associated with severe neurodevelopmental defects in newborns through poorly defined mechanisms. Here, we established a zebrafish in vivo model of ZIKV infection to circumvent limitations of existing mammalian models. Leveraging the unique tractability of this system, we gained unprecedented access to the ZIKV-infected brain at early developmental stages. The infection of zebrafish larvae with ZIKV phenocopied the disease in mammals including a reduced head area and neural progenitor cells (NPC) infection and depletion. Moreover, transcriptomic analyses of NPCs isolated from ZIKV-infected embryos revealed a distinct dysregulation of genes involved in survival and neuronal differentiation, including downregulation of the expression of the glutamate transporter vglut1, resulting in an altered glutamatergic network in the brain. Mechanistically, ectopic expression of ZIKV protein NS4A in the larvae recapitulated the morphological defects observed in infected animals, identifying NS4A as a key determinant of neurovirulence and a promising antiviral target for developing therapies.
Copyright: © 2024 Sow et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
MeSH terms
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Animals
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Brain / metabolism
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Brain / pathology
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Brain / virology
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Disease Models, Animal*
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Humans
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Neural Stem Cells / metabolism
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Neural Stem Cells / pathology
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Neural Stem Cells / virology
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Neurogenesis / physiology
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Neurons / metabolism
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Neurons / pathology
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Neurons / virology
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Viral Nonstructural Proteins / genetics
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Viral Nonstructural Proteins / metabolism
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Zebrafish*
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Zika Virus Infection* / metabolism
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Zika Virus Infection* / pathology
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Zika Virus Infection* / virology
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Zika Virus* / physiology
Substances
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Viral Nonstructural Proteins
Grants and funding
A.A.S has received PhD fellowships from the Fonds de Recherche du Québec-Nature et Technologies (FRQNT;
https://frq.gouv.qc.ca/nature-et-technologies/), the Armand-Frappier Foundation (
https://fondationafrappier.ca/) and the Center of Excellence in Research on Orphan Diseases-Courtois Foundation (CERMO-FC;
https://www.cermofc.uqam.ca/). P.J was supported by a CERMO-FC scholarship. L.C.C is receiving a research scholar (Senior) salary support from Fonds de Recherche du Québec-Santé (FRQS;
https://frq.gouv.qc.ca/sante/). S.P holds an FRQS Junior 2 research scholar salary award and the Anna Sforza Djoukhadjian Research Chair. This study was supported by the Canada Foundation for Innovation (CFI; #37512, to S.P;
https://www.innovation.ca/), by the Canadian Institutes for Health Research (CIHR; PJT 190064 to L.C.C and S.P, and PJT 177940 to S.P;
https://cihr-irsc.gc.ca/), by an Acceleration grant from CERMO-FC to S.P and L.C.C, and by a Azrieli Future Leader in Canadian Brain Research grant from Brain Canada Foundation (
https://braincanada.ca/fr/) through the Canada Brain Research Fund, with the financial support of Health Canada and the Azrieli Foundation awarded to L.C.C. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.