Type I IFNs decrease SARS-CoV-2 replication in human cardiomyocytes

Shambhabi Chatterjee (Hannover)1, V. Durán (Hannover)2, E. Nikolouli (Hannover)3, A. Pavlou (Hannover)2, A. Korte (Hannover)1, U. Kalinke (Hannover)2, N. Lachmann (Hannover)3, C. Bär (Hannover)1, T. Thum (Hannover)1

1Medizinische Hochschule Hannover Institut für Molekulare und Translationale Therapiestrategien, OE-8886 Hannover, Deutschland; 2Institute for Experimental Infection Research, TWINCORE Centre for Experimental and Clinical Infection Research Hannover, Deutschland; 3Hannover Medical School (MHH) Department for Pediatric Pneumology, Allergology and Neonatology Hannover, Deutschland

 

Aims: COVID-19 remains a severe concern for global health and long-COVID symptoms are on the rise. Despite the vaccinations that can efficiently prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, there are still no effective treatments of the disease once people are infected. Elevated expression of the entry receptor angiotensin-converting enzyme 2 (ACE2) on cardiac cells of heart patients make them more susceptible to SARS-CoV-2 infection. Moreover, the cellular basis of COVID-19 severity in patients with deficiencies in type I interferon (IFN) immunity remains unclear. In this project, we analyzed virus replication and cytokine production in SARS-CoV-2 exposed cardiomyocytes that were differentiated from IFN receptor subunit 1 (IFNAR1) competent (IFNAR1comp) or deficient (IFNAR1def) human induced pluripotent stem cells (hiPSCs).

Methods & results: We first differentiated hiPSCs into cardiomyocytes (hiPSC-CMs) from both IFNAR1comp or IFNAR1def and analyzed expressions of well-known cardiac-specific markers (TNNI1, RYR2, MYH7, MYH6, IRX4, HCN1, CORIN) using qPCR. The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) was expressed higher in IFNAR1comp hiPSC-CMs compared to IFNAR1def while expression of the neuropilin 1 receptor (NRP1) was moderate in both conditions as measured by qPCR and/or flow cytometry. However, on further infection with the SARS-CoV-2 viral particles a higher viral replication was observed in IFNAR1def than IFNAR1comp cells when analyzed via immunostaining and plaque assay. Furthermore, exogenous IFNα mitigated infection in IFNAR1comp, but not in IFNAR1def cardiomyocytes again measured via immunostaining and plaque assay.

Conclusion: We observed that IFNAR1 expression does not have a significant effect on SARS-CoV-2 infection in hiPSC-CMs, however, it does decrease viral replication in these cells, as demonstrated by lower SARS-CoV-2 titers in IFNAR1comp than in IFNAR1def hiPSC-CMs. Taken together, the data generated in this study indicates that overall, type I IFNs decrease SARS-CoV-2 replication in hiPSC-CMs and this might help to establish new potential therapeutic strategies for protecting the heart from acute COVID-19.

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