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Selectively expressing SARS-CoV-2 Spike protein S1 subunit in cardiomyocytes induces cardiac hypertrophy in mice

Steven G. Negron, Chase W. Kessinger, Bing Xu, William T. Pu, View ORCID ProfileZhiqiang Lin
doi: https://doi.org/10.1101/2021.06.20.448993
Steven G. Negron
1Masonic Medical Research Institute, 2150 Bleecker Street, Utica, NY 13501
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Chase W. Kessinger
1Masonic Medical Research Institute, 2150 Bleecker Street, Utica, NY 13501
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Bing Xu
1Masonic Medical Research Institute, 2150 Bleecker Street, Utica, NY 13501
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William T. Pu
2Boston Children’s Hospital, 300 Longwood Ave, Boston, MA, 02115
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Zhiqiang Lin
1Masonic Medical Research Institute, 2150 Bleecker Street, Utica, NY 13501
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  • ORCID record for Zhiqiang Lin
  • For correspondence: zlin@mmri.edu
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Abstract

Cardiac injury is common in hospitalized COVID-19 patients and portends poorer prognosis and higher mortality. To better understand how SARS-CoV-2 (CoV-2) damages the heart, it is critical to elucidate the biology of CoV-2 encoded proteins, each of which may play multiple pathological roles. For example, CoV-2 Spike glycoprotein (CoV-2-S) not only engages ACE2 to mediate virus infection, but also directly impairs endothelial function and can trigger innate immune responses in cultured murine macrophages. Here we tested the hypothesis that CoV-2-S damages the heart by activating cardiomyocyte (CM) innate immune responses. HCoV-NL63 is another human coronavirus with a Spike protein (NL63-S) that also engages ACE2 for virus entry but is known to only cause moderate respiratory symptoms. We found that CoV-2-S and not NL63-S interacted with Toll-like receptor 4 (TLR4), a crucial pattern recognition receptor that responsible for detecting pathogen and initiating innate immune responses. Our data show that the S1 subunit of CoV-2-S (CoV-2-S1) interacts with the extracellular leucine rich repeats-containing domain of TLR4 and activates NF-kB. To investigate the possible pathological role of CoV-2-S1 in the heart, we generated a construct that expresses membrane-localized CoV-2-S1 (S1-TM). AAV9-mediated, selective expression of the S1-TM in CMs caused heart dysfunction, induced hypertrophic remodeling, and elicited cardiac inflammation. Since CoV-2-S does not interact with murine ACE2, our study presents a novel ACE2-independent pathological role of CoV-2-S, and suggests that the circulating CoV-2-S1 is a TLR4-recognizable alarmin that may harm the CMs by triggering their innate immune responses.

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-ND 4.0 International license.
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Posted June 20, 2021.
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Selectively expressing SARS-CoV-2 Spike protein S1 subunit in cardiomyocytes induces cardiac hypertrophy in mice
Steven G. Negron, Chase W. Kessinger, Bing Xu, William T. Pu, Zhiqiang Lin
bioRxiv 2021.06.20.448993; doi: https://doi.org/10.1101/2021.06.20.448993
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Selectively expressing SARS-CoV-2 Spike protein S1 subunit in cardiomyocytes induces cardiac hypertrophy in mice
Steven G. Negron, Chase W. Kessinger, Bing Xu, William T. Pu, Zhiqiang Lin
bioRxiv 2021.06.20.448993; doi: https://doi.org/10.1101/2021.06.20.448993

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