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Modeling SARS-CoV-2 infection and its individual differences with ACE2-expressing human iPS cells

Emi Sano, Ayaka Sakamoto, Natsumi Mimura, Ai Hirabayashi, Yukiko Muramoto, Takeshi Noda, Takuya Yamamoto, Kazuo Takayama
doi: https://doi.org/10.1101/2021.02.22.432218
Emi Sano
1Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
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Ayaka Sakamoto
1Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
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Natsumi Mimura
1Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
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Ai Hirabayashi
2Laboratory of Ultrastructural Virology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
3CREST, Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan
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Yukiko Muramoto
2Laboratory of Ultrastructural Virology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
3CREST, Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan
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Takeshi Noda
2Laboratory of Ultrastructural Virology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
3CREST, Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan
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Takuya Yamamoto
1Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
4Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto 606-8501 Japan
5Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto 606-8507, Japan
6AMED-CREST, Japan Agency for Medical Research and Development (AMED), Tokyo 100-0004, Japan
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Kazuo Takayama
1Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
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  • For correspondence: kazuo.takayama@cira.kyoto-u.ac.jp
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Abstract

Genetic differences are a primary reason for differences in the susceptibility and severity of coronavirus disease 2019 (COVID-19). Because induced pluripotent stem (iPS) cells maintain the genetic information of the donor, they can be used to model individual differences in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vitro. Notably, undifferentiated human iPS cells themselves cannot be infected bySARS-CoV-2. Using adenovirus vectors, here we found that human iPS cells expressing the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) (ACE2-iPS cells) can be infected with SARS-CoV-2. In infected ACE2-iPS cells, the expression of SARS-CoV-2 nucleocapsid protein, the budding of viral particles, the production of progeny virus, double membrane spherules, and double-membrane vesicles were confirmed. We also evaluated COVID-19 therapeutic drugs in ACE2-iPS cells and confirmed the strong antiviral effects of Remdesivir, EIDD-2801, and interferon-beta. In addition, we performed SARS-CoV-2 infection experiments on ACE2-iPS/ES cells from 8 individuals. Male iPS/ES cells were more capable of producing the virus as compared with female iPS/ES cells. These findings suggest that ACE2-iPS cells can not only reproduce individual differences in SARS-CoV-2 infection in vitro, but they are also a useful resource to clarify the causes of individual differences in COVID-19 due to genetic differences.

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Competing Interest Statement

The authors have declared no competing interest.

Copyright 
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 4.0 International license.
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Posted February 22, 2021.
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Modeling SARS-CoV-2 infection and its individual differences with ACE2-expressing human iPS cells
Emi Sano, Ayaka Sakamoto, Natsumi Mimura, Ai Hirabayashi, Yukiko Muramoto, Takeshi Noda, Takuya Yamamoto, Kazuo Takayama
bioRxiv 2021.02.22.432218; doi: https://doi.org/10.1101/2021.02.22.432218
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Modeling SARS-CoV-2 infection and its individual differences with ACE2-expressing human iPS cells
Emi Sano, Ayaka Sakamoto, Natsumi Mimura, Ai Hirabayashi, Yukiko Muramoto, Takeshi Noda, Takuya Yamamoto, Kazuo Takayama
bioRxiv 2021.02.22.432218; doi: https://doi.org/10.1101/2021.02.22.432218

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