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
Affiliations
José Alexandre Salerno
Institute of Biomedical Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
Thayana Torquato
D’Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil
Jairo R. Temerozo
National Institute for Science and Technology on Neuroimmunomodulation (INCT/NIM), Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil
Livia Goto-Silva
D’Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil
Karina Karmirian
Institute of Biomedical Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
Mayara A. Mendes
D’Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil
Carolina Q. Sacramento
Immunopharmacology Laboratory, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil
Natalia Fintelman-Rodrigues
Immunopharmacology Laboratory, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil
Letícia R Q. Souza
D’Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil
Isis M. Ornelas
D’Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil
Carla P. Veríssimo
Institute of Biomedical Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
Luiz Guilherme H S. Aragão
D’Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil
Gabriela Vitória
D’Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil
Carolina S G. Pedrosa
D’Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil
Suelen da Silva Gomes Dias
Immunopharmacology Laboratory, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil
Vinicius Cardoso Soares
Institute of Biomedical Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
Teresa Puig-Pijuan
D’Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil
Vinícius Salazar
Department of Systems and Computer Engineering, COPPE, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
Rafael Dariolli
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
Diogo Biagi
PluriCell Biotech, São Paulo, Brazil
Daniel R. Furtado
D’Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil
Luciana Barreto Chiarini
Carlos Chagas Filho Institute of Biophysics (IBCCF), Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
Helena L. Borges
Institute of Biomedical Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
Patrícia T. Bozza
Immunopharmacology Laboratory, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil
Marilia Zaluar P. Guimarães
Institute of Biomedical Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
Thiago M.L. Souza
Immunopharmacology Laboratory, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil
Stevens K. Rehen
D’Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil
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.
