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The SARS-CoV-2 Spike protein disrupts human cardiac pericytes function through CD147-receptor-mediated signalling: a potential non-infective mechanism of COVID-19 microvascular disease

View ORCID ProfileElisa Avolio, Michele Carrabba, Rachel Milligan, Maia Kavanagh Williamson, Antonio P Beltrami, Kapil Gupta, Karen T Elvers, Monica Gamez, Rebecca Foster, Kathleen Gillespie, Fergus Hamilton, David Arnold, Imre Berger, Massimo Caputo, Andrew D Davidson, Darryl Hill, Paolo Madeddu
doi: https://doi.org/10.1101/2020.12.21.423721
Elisa Avolio
1Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, United Kingdom
PhD
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  • ORCID record for Elisa Avolio
  • For correspondence: elisa.avolio@bristol.ac.uk mdprm@bristol.ac.uk
Michele Carrabba
1Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, United Kingdom
PhD
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Rachel Milligan
2School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
PhD
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Maia Kavanagh Williamson
2School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
PhD
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Antonio P Beltrami
3Department of Pathology, University of Udine, Udine, Italy
MD PhD
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Kapil Gupta
4School of Biochemistry, University of Bristol, Bristol, United Kingdom
PhD
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Karen T Elvers
5Medicines Discovery Institute, Cardiff University, Cardiff, United Kingdom
PhD
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Monica Gamez
1Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, United Kingdom
PhD
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Rebecca Foster
1Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, United Kingdom
PhD
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Kathleen Gillespie
1Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, United Kingdom
PhD
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Fergus Hamilton
1Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, United Kingdom
PhD
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David Arnold
1Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, United Kingdom
PhD
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Imre Berger
4School of Biochemistry, University of Bristol, Bristol, United Kingdom
6Max Planck Bristol Centre for Minimal Biology, University of Bristol, Bristol, United Kingdom
PhD
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Massimo Caputo
1Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, United Kingdom
MD
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Andrew D Davidson
2School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
PhD
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Darryl Hill
2School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
PhD
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Paolo Madeddu
1Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, United Kingdom
MD
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  • For correspondence: elisa.avolio@bristol.ac.uk mdprm@bristol.ac.uk
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ABSTRACT

Severe coronavirus disease 2019 (COVID-19) manifests as a life-threatening microvascular syndrome. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the Spike (S) protein to engage with its receptors and infect host cells. To date, it is still not known whether heart vascular pericytes (PCs) are infected by SARS-CoV-2, and if the S protein alone provokes PC dysfunction. Here, we aimed to investigate the effects of the S protein on primary human cardiac PC signalling and function. Results show, for the first time, that cardiac PCs are not permissive to SARS-CoV-2 infection in vitro, whilst a recombinant S protein alone elicits functional alterations in PCs. This was documented as: (1) increased migration, (2) reduced ability to support endothelial cell (EC) network formation on Matrigel, (3) secretion of pro-inflammatory molecules typically involved in the cytokine storm, and (4) production of pro-apoptotic factors responsible for EC death. Next, adopting a blocking strategy against the S protein receptors angiotensin-converting enzyme 2 (ACE2) and CD147, we discovered that the S protein stimulates the phosphorylation/activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) through the CD147 receptor, but not ACE2, in PCs. The neutralisation of CD147, either using a blocking antibody or mRNA silencing, reduced ERK1/2 activation and rescued PC function in the presence of the S protein. In conclusion, our findings suggest that circulating S protein prompts vascular PC dysfunction, potentially contributing to establishing microvascular injury in organs distant from the site of infection. This mechanism may have clinical and therapeutic implications.

Clinical perspective

  • Severe COVID-19 manifests as a microvascular syndrome, but whether SARS-CoV-2 infects and damages heart vascular pericytes (PCs) remains unknown.

  • We provide evidence that cardiac PCs are not infected by SARS-CoV-2. Importantly, we show that the recombinant S protein alone elicits cellular signalling through the CD147 receptor in cardiac PCs, thereby inducing cell dysfunction and microvascular disruption in vitro.

  • This study suggests that soluble S protein can potentially propagate damage to organs distant from sites of infection, promoting microvascular injury. Blocking the CD147 receptor in patients may help protect the vasculature not only from infection, but also from the collateral damage caused by the S protein.

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. All rights reserved. No reuse allowed without permission.
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Posted July 20, 2021.
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The SARS-CoV-2 Spike protein disrupts human cardiac pericytes function through CD147-receptor-mediated signalling: a potential non-infective mechanism of COVID-19 microvascular disease
Elisa Avolio, Michele Carrabba, Rachel Milligan, Maia Kavanagh Williamson, Antonio P Beltrami, Kapil Gupta, Karen T Elvers, Monica Gamez, Rebecca Foster, Kathleen Gillespie, Fergus Hamilton, David Arnold, Imre Berger, Massimo Caputo, Andrew D Davidson, Darryl Hill, Paolo Madeddu
bioRxiv 2020.12.21.423721; doi: https://doi.org/10.1101/2020.12.21.423721
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The SARS-CoV-2 Spike protein disrupts human cardiac pericytes function through CD147-receptor-mediated signalling: a potential non-infective mechanism of COVID-19 microvascular disease
Elisa Avolio, Michele Carrabba, Rachel Milligan, Maia Kavanagh Williamson, Antonio P Beltrami, Kapil Gupta, Karen T Elvers, Monica Gamez, Rebecca Foster, Kathleen Gillespie, Fergus Hamilton, David Arnold, Imre Berger, Massimo Caputo, Andrew D Davidson, Darryl Hill, Paolo Madeddu
bioRxiv 2020.12.21.423721; doi: https://doi.org/10.1101/2020.12.21.423721

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