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ApoE-Isoform-Dependent SARS-CoV-2 Neurotropism and Cellular Response

ApoE4, a strong genetic risk factor for Alzheimer disease, has been associated with increased risk for severe COVID-19. However, it is unclear whether ApoE4 alters COVID-19 susceptibility or severity, and the role of direct viral infection in brain cells remains obscure. We tested the neurotropism o...

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Autores principales: Wang, Cheng, Zhang, Mingzi, Garcia, Gustavo, Tian, E., Cui, Qi, Chen, Xianwei, Sun, Guihua, Wang, Jinhui, Arumugaswami, Vaithilingaraja, Shi, Yanhong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832490/
https://www.ncbi.nlm.nih.gov/pubmed/33450186
http://dx.doi.org/10.1016/j.stem.2020.12.018
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author Wang, Cheng
Zhang, Mingzi
Garcia, Gustavo
Tian, E.
Cui, Qi
Chen, Xianwei
Sun, Guihua
Wang, Jinhui
Arumugaswami, Vaithilingaraja
Shi, Yanhong
author_facet Wang, Cheng
Zhang, Mingzi
Garcia, Gustavo
Tian, E.
Cui, Qi
Chen, Xianwei
Sun, Guihua
Wang, Jinhui
Arumugaswami, Vaithilingaraja
Shi, Yanhong
author_sort Wang, Cheng
collection PubMed
description ApoE4, a strong genetic risk factor for Alzheimer disease, has been associated with increased risk for severe COVID-19. However, it is unclear whether ApoE4 alters COVID-19 susceptibility or severity, and the role of direct viral infection in brain cells remains obscure. We tested the neurotropism of SARS-CoV2 in human-induced pluripotent stem cell (hiPSC) models and observed low-grade infection of neurons and astrocytes that is boosted in neuron-astrocyte co-cultures and organoids. We then generated isogenic ApoE3/3 and ApoE4/4 hiPSCs and found an increased rate of SARS-CoV-2 infection in ApoE4/4 neurons and astrocytes. ApoE4 astrocytes exhibited enlarged size and elevated nuclear fragmentation upon SARS-CoV-2 infection. Finally, we show that remdesivir treatment inhibits SARS-CoV2 infection of hiPSC neurons and astrocytes. These findings suggest that ApoE4 may play a causal role in COVID-19 severity. Understanding how risk factors impact COVID-19 susceptibility and severity will help us understand the potential long-term effects in different patient populations.
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spelling pubmed-78324902021-01-26 ApoE-Isoform-Dependent SARS-CoV-2 Neurotropism and Cellular Response Wang, Cheng Zhang, Mingzi Garcia, Gustavo Tian, E. Cui, Qi Chen, Xianwei Sun, Guihua Wang, Jinhui Arumugaswami, Vaithilingaraja Shi, Yanhong Cell Stem Cell Short Article ApoE4, a strong genetic risk factor for Alzheimer disease, has been associated with increased risk for severe COVID-19. However, it is unclear whether ApoE4 alters COVID-19 susceptibility or severity, and the role of direct viral infection in brain cells remains obscure. We tested the neurotropism of SARS-CoV2 in human-induced pluripotent stem cell (hiPSC) models and observed low-grade infection of neurons and astrocytes that is boosted in neuron-astrocyte co-cultures and organoids. We then generated isogenic ApoE3/3 and ApoE4/4 hiPSCs and found an increased rate of SARS-CoV-2 infection in ApoE4/4 neurons and astrocytes. ApoE4 astrocytes exhibited enlarged size and elevated nuclear fragmentation upon SARS-CoV-2 infection. Finally, we show that remdesivir treatment inhibits SARS-CoV2 infection of hiPSC neurons and astrocytes. These findings suggest that ApoE4 may play a causal role in COVID-19 severity. Understanding how risk factors impact COVID-19 susceptibility and severity will help us understand the potential long-term effects in different patient populations. Elsevier Inc. 2021-02-04 2021-01-04 /pmc/articles/PMC7832490/ /pubmed/33450186 http://dx.doi.org/10.1016/j.stem.2020.12.018 Text en © 2020 Elsevier Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Short Article
Wang, Cheng
Zhang, Mingzi
Garcia, Gustavo
Tian, E.
Cui, Qi
Chen, Xianwei
Sun, Guihua
Wang, Jinhui
Arumugaswami, Vaithilingaraja
Shi, Yanhong
ApoE-Isoform-Dependent SARS-CoV-2 Neurotropism and Cellular Response
title ApoE-Isoform-Dependent SARS-CoV-2 Neurotropism and Cellular Response
title_full ApoE-Isoform-Dependent SARS-CoV-2 Neurotropism and Cellular Response
title_fullStr ApoE-Isoform-Dependent SARS-CoV-2 Neurotropism and Cellular Response
title_full_unstemmed ApoE-Isoform-Dependent SARS-CoV-2 Neurotropism and Cellular Response
title_short ApoE-Isoform-Dependent SARS-CoV-2 Neurotropism and Cellular Response
title_sort apoe-isoform-dependent sars-cov-2 neurotropism and cellular response
topic Short Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832490/
https://www.ncbi.nlm.nih.gov/pubmed/33450186
http://dx.doi.org/10.1016/j.stem.2020.12.018
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