Inhibition of SARS-CoV-2 infection in human iPSC-derived cardiomyocytes by targeting the Sigma-1 receptor disrupts cytoarchitecture and beating

José Alexandre Salerno; Thayana Torquato; Jairo R Temerozo; Livia Goto-Silva; Karina Karmirian; Mayara A Mendes; Carolina Q Sacramento; Natalia Fintelman-Rodrigues; Letícia R Q Souza; Isis M Ornelas; Carla P Veríssimo; Luiz Guilherme H S Aragão; Gabriela Vitória; Carolina S G Pedrosa; Suelen da Silva Gomes Dias; Vinicius Cardoso Soares; Teresa Puig-Pijuan; Vinícius Salazar; Rafael Dariolli; Diogo Biagi; Daniel R Furtado; Luciana Barreto Chiarini; Helena L Borges; Patrícia T Bozza; Marilia Zaluar P Guimarães; Thiago M L Souza; Stevens K Rehen

doi:10.7717/peerj.12595

Inhibition of SARS-CoV-2 infection in human iPSC-derived cardiomyocytes by targeting the Sigma-1 receptor disrupts cytoarchitecture and beating

PeerJ. 2021 Dec 20:9:e12595. doi: 10.7717/peerj.12595. eCollection 2021.

Authors

José Alexandre Salerno^#^{1

2}, Thayana Torquato^#², Jairo R Temerozo^{3

4}, Livia Goto-Silva², Karina Karmirian^{1

2}, Mayara A Mendes², Carolina Q Sacramento^{5

6}, Natalia Fintelman-Rodrigues^{5

6}, Letícia R Q Souza², Isis M Ornelas², Carla P Veríssimo¹, Luiz Guilherme H S Aragão², Gabriela Vitória², Carolina S G Pedrosa², Suelen da Silva Gomes Dias⁵, Vinicius Cardoso Soares^{1

5}, Teresa Puig-Pijuan^{2

7}, Vinícius Salazar⁸, Rafael Dariolli^{9

10}, Diogo Biagi¹⁰, Daniel R Furtado², Luciana Barreto Chiarini⁷, Helena L Borges¹, Patrícia T Bozza⁵, Marilia Zaluar P Guimarães^{1

2}, Thiago M L Souza^{5

6}, Stevens K Rehen^{2

11}

Affiliations

¹ Institute of Biomedical Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.
² D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil.
³ National Institute for Science and Technology on Neuroimmunomodulation (INCT/NIM), Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil.
⁴ Laboratory on Thymus Research, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil.
⁵ Immunopharmacology Laboratory, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil.
⁶ National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil.
⁷ Carlos Chagas Filho Institute of Biophysics (IBCCF), Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.
⁸ Department of Systems and Computer Engineering, COPPE, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.
⁹ Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
¹⁰ PluriCell Biotech, São Paulo, Brazil.
¹¹ Department of Genetics, Institute of Biology, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

^# Contributed equally.

Abstract

SARS-CoV-2 infects cardiac cells and causes heart dysfunction. Conditions such as myocarditis and arrhythmia have been reported in COVID-19 patients. The Sigma-1 receptor (S1R) is a ubiquitously expressed chaperone that plays a central role in cardiomyocyte function. S1R has been proposed as a therapeutic target because it may affect SARS-CoV-2 replication; however, the impact of the inhibition of S1R in human cardiomyocytes remains to be described. In this study, we investigated the consequences of S1R inhibition in iPSC-derived human cardiomyocytes (hiPSC-CM). SARS-CoV-2 infection in hiPSC-CM was productive and reduced cell survival. S1R inhibition decreased both the number of infected cells and viral particles after 48 hours. S1R inhibition also prevented the release of pro-inflammatory cytokines and cell death. Although the S1R antagonist NE-100 triggered those protective effects, it compromised cytoskeleton integrity by downregulating the expression of structural-related genes and reducing beating frequency. Our findings suggest that the detrimental effects of S1R inhibition in human cardiomyocytes' integrity may abrogate its therapeutic potential against COVID and should be carefully considered.

Keywords: Cardiomyocyte; IPSC; SARS-CoV-2; Sigma-1 Receptor.

Grants and funding

This work was supported by intramural grants from D’Or Institute for Research and Education. Students’ scholarships and fellowships were paid by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) or Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.