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SARS-CoV-2 direct cardiac damage through spike-mediated cardiomyocyte fusion

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Author information

Affiliations

  • 1. Discovery Engine/Program for Hypoplastic Left Heart Syndrome, Mayo Clinic, Rochester, Minnesota 55905, USA
      Authors
    • Schneider J 1
    • Pease D 1
    (2 authors)
  • 2. Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA
      Authors
    • Navaratnarajah C 2
    • Barkhymer A 2
    • Cattaneo R 2
    (3 authors)
  • 3. Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA
      Authors
    • Halfmann P 3
    • Kawaoka Y 3
    (2 authors)
  • 4. Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, Minnesota 55905, USA
      Authors
    • Clemens D 4
    • Ye D 4
    • Kim C 4
    • Ackerman M 4
    (4 authors)
  • 5. Spectrum Health, Blodgett Hospital Pathology, Grand Rapids, Michigan 49506, USA
      Authors
    • Cohle S 5
    (1 author)
    • Show all (9)

Preprint from Research Square, 30 Oct 2020
https://doi.org/10.21203/rs.3.rs-95587/v1 PPR: PPR232448 

Preprint v1

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Preprint version history

  • Version 1 [30 Oct 2020]

Abstract 

Abstract

Viruses spread between hosts through particles, but within hosts, viral genomes can spread from cell to cell through fusion, evading antiviral defenses and obviating costly infectious virion production1-3. Billions of electromechanically coupled cardiomyocytes (CMs) make myocardium inherently vulnerable to pathological electromechanical short circuits caused by intercellular viral spread 4-6. Beyond respiratory illness, COVID-19 affects the heart7 and cardiac injury and arrhythmias are serious public health concerns8-12. By studying myocardium of a young woman who died suddenly, diagnosed postmortem with COVID-19, we discovered highly focal myocardial SARS-CoV-2 infection spreading from one CM to another through intercellular junctions identified by highly concentrated sarcolemmal t-tubule viral spike glycoprotein. SARS-CoV-2 permissively infected beating human induced pluripotent stem cell (hiPSC)-CMs building multinucleated cardiomyotubes (CMTs) through cell type-specific fusion driven by proteolytically-activated spike glycoprotein. Recombinant spike glycoprotein, co-localizing to sarcolemma and sarcoplasmic reticulum, produced multinucleated CMTs with pathological structure, electrophysiology and Ca2+ excitation-contraction coupling. Blocking cleavage, a peptide-based protease inhibitor neutralized SARS-CoV-2 spike glycoprotein pathogenicity. We conclude that SARS-CoV-2 spike glycoprotein, efficiently primed, activated and strategically poised during biosynthesis, can exploit the CM’s inherent membranous connectivities to drive heart damage directly, uncoupling clinically common myocardial injury from lymphocytic myocarditis, often suspected but rarely confirmed in COVID-19.

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Read article at publisher's site: https://doi.org/10.21203/rs.3.rs-95587/v1

Read article for free, from open access legal sources, via Unpaywall: https://www.researchsquare.com/article/rs-95587/latest.pdfUnpaywall

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