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Niclosamide rescues microcephaly in a humanized in vivo model of Zika infection using human induced neural stem cells

Zika virus (ZIKV) is a mosquito-transmitted flavivirus with a causative link to microcephaly, a condition resulting in reduced cranial size and brain abnormalities. Despite recent progress, there is a current lack of in vivo models that permit the study of systemic virus on human neurons in a develo...

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Autores principales: Cairns, Dana M., Boorgu, Devi Sai Sri Kavya, Levin, Michael, Kaplan, David L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829514/
https://www.ncbi.nlm.nih.gov/pubmed/29378701
http://dx.doi.org/10.1242/bio.031807
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author Cairns, Dana M.
Boorgu, Devi Sai Sri Kavya
Levin, Michael
Kaplan, David L.
author_facet Cairns, Dana M.
Boorgu, Devi Sai Sri Kavya
Levin, Michael
Kaplan, David L.
author_sort Cairns, Dana M.
collection PubMed
description Zika virus (ZIKV) is a mosquito-transmitted flavivirus with a causative link to microcephaly, a condition resulting in reduced cranial size and brain abnormalities. Despite recent progress, there is a current lack of in vivo models that permit the study of systemic virus on human neurons in a developing organism that replicates the pathophysiology of human disease. Furthermore, no treatment to date has been reported to reduce ZIKV-induced microcephaly. We tested the effects of ZIKV on human induced neural stem cells (hiNSCs) in vitro and found that infected hiNSCs secrete inflammatory cytokines, display altered differentiation, and become apoptotic. We also utilized this in vitro system to assess the therapeutic effects of niclosamide, an FDA-approved anthelminthic, and found that it decreases ZIKV production, partially restores differentiation, and prevents apoptosis in hiNSCs. We intracranially injected hiNSCs into developing chicks, subjected them to systemic ZIKV infection via the chorioallantoic membrane (CAM), a tissue similar in structure and function to the mammalian placenta, and found that humanized ZIKV-infected embryos developed severe microcephaly including smaller crania, decreased forebrain volume and enlarged ventricles. Lastly, we utilized this humanized model to show that CAM-delivery of niclosamide can partially rescue ZIKV-induced microcephaly and attenuate infection of hiNSCs in vivo. This article has an associated First Person interview with the first author of the paper.
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spelling pubmed-58295142018-02-28 Niclosamide rescues microcephaly in a humanized in vivo model of Zika infection using human induced neural stem cells Cairns, Dana M. Boorgu, Devi Sai Sri Kavya Levin, Michael Kaplan, David L. Biol Open Research Article Zika virus (ZIKV) is a mosquito-transmitted flavivirus with a causative link to microcephaly, a condition resulting in reduced cranial size and brain abnormalities. Despite recent progress, there is a current lack of in vivo models that permit the study of systemic virus on human neurons in a developing organism that replicates the pathophysiology of human disease. Furthermore, no treatment to date has been reported to reduce ZIKV-induced microcephaly. We tested the effects of ZIKV on human induced neural stem cells (hiNSCs) in vitro and found that infected hiNSCs secrete inflammatory cytokines, display altered differentiation, and become apoptotic. We also utilized this in vitro system to assess the therapeutic effects of niclosamide, an FDA-approved anthelminthic, and found that it decreases ZIKV production, partially restores differentiation, and prevents apoptosis in hiNSCs. We intracranially injected hiNSCs into developing chicks, subjected them to systemic ZIKV infection via the chorioallantoic membrane (CAM), a tissue similar in structure and function to the mammalian placenta, and found that humanized ZIKV-infected embryos developed severe microcephaly including smaller crania, decreased forebrain volume and enlarged ventricles. Lastly, we utilized this humanized model to show that CAM-delivery of niclosamide can partially rescue ZIKV-induced microcephaly and attenuate infection of hiNSCs in vivo. This article has an associated First Person interview with the first author of the paper. The Company of Biologists Ltd 2018-01-15 /pmc/articles/PMC5829514/ /pubmed/29378701 http://dx.doi.org/10.1242/bio.031807 Text en © 2018. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Cairns, Dana M.
Boorgu, Devi Sai Sri Kavya
Levin, Michael
Kaplan, David L.
Niclosamide rescues microcephaly in a humanized in vivo model of Zika infection using human induced neural stem cells
title Niclosamide rescues microcephaly in a humanized in vivo model of Zika infection using human induced neural stem cells
title_full Niclosamide rescues microcephaly in a humanized in vivo model of Zika infection using human induced neural stem cells
title_fullStr Niclosamide rescues microcephaly in a humanized in vivo model of Zika infection using human induced neural stem cells
title_full_unstemmed Niclosamide rescues microcephaly in a humanized in vivo model of Zika infection using human induced neural stem cells
title_short Niclosamide rescues microcephaly in a humanized in vivo model of Zika infection using human induced neural stem cells
title_sort niclosamide rescues microcephaly in a humanized in vivo model of zika infection using human induced neural stem cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829514/
https://www.ncbi.nlm.nih.gov/pubmed/29378701
http://dx.doi.org/10.1242/bio.031807
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