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Cyclosporine A Inhibits Viral Infection and Release as Well as Cytokine Production in Lung Cells by Three SARS-CoV-2 Variants

In December 2019, a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started spreading worldwide causing the coronavirus disease 2019 (COVID-19) pandemic. The hyperactivation of the immune system has been proposed to account for disease severity and death in COVID-19 patients. Despit...

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Autores principales: Fenizia, Claudio, Galbiati, Silvia, Vanetti, Claudia, Vago, Riccardo, Clerici, Mario, Tacchetti, Carlo, Daniele, Tiziana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8729790/
https://www.ncbi.nlm.nih.gov/pubmed/34985303
http://dx.doi.org/10.1128/spectrum.01504-21
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author Fenizia, Claudio
Galbiati, Silvia
Vanetti, Claudia
Vago, Riccardo
Clerici, Mario
Tacchetti, Carlo
Daniele, Tiziana
author_facet Fenizia, Claudio
Galbiati, Silvia
Vanetti, Claudia
Vago, Riccardo
Clerici, Mario
Tacchetti, Carlo
Daniele, Tiziana
author_sort Fenizia, Claudio
collection PubMed
description In December 2019, a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started spreading worldwide causing the coronavirus disease 2019 (COVID-19) pandemic. The hyperactivation of the immune system has been proposed to account for disease severity and death in COVID-19 patients. Despite several approaches having been tested, no therapeutic protocol has been approved. Given that Cyclosporine A (CsA) is well-known to exert a strong antiviral activity on several viral strains and an anti-inflammatory role in different organs with relevant benefits in diverse pathological contexts, we tested its effects on SARS-CoV-2 infection of lung cells. We found that treatment with CsA either before or after infection of CaLu3 cells by three SARS-CoV-2 variants: (i) reduces the expression of both viral RNA and proteins in infected cells; (ii) decreases the number of progeny virions released by infected cells; (iii) dampens the virus-triggered synthesis of cytokines (including IL-6, IL-8, IL1α and TNF-α) that are involved in cytokine storm in patients. Altogether, these data provide a rationale for CsA repositioning for the treatment of severe COVID-19 patients. IMPORTANCE SARS-CoV-2 is the most recently identified member of the betacoronavirus genus responsible for the COVID-19 pandemic. Repurposing of available drugs has been a “quick and dirty” approach to try to reduce mortality and severe symptoms in affected patients initially, and can still represent an undeniable and valuable approach to face COVID-19 as the continuous appearance and rapid diffusion of more “aggressive”/transmissible variants, capable of eluding antibody neutralization, challenges the effectiveness of some anti-SARS-CoV-2 vaccines. Here, we tested a known antiviral and anti-inflammatory drug, Cyclosporine A (CsA), and found that it dampens viral infection and cytokine release from lung cells upon exposure to three different SARS-CoV-2 variants. Knock down of the main intracellular target of CsA, Cyclophilin A, does not phenocopy the drug inhibition of viral infection. Altogether, these findings shed new light on the cellular mechanisms of SARS-CoV-2 infection and provide the rationale for CsA repositioning to treat severe COVID-19 patients.
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spelling pubmed-87297902022-01-06 Cyclosporine A Inhibits Viral Infection and Release as Well as Cytokine Production in Lung Cells by Three SARS-CoV-2 Variants Fenizia, Claudio Galbiati, Silvia Vanetti, Claudia Vago, Riccardo Clerici, Mario Tacchetti, Carlo Daniele, Tiziana Microbiol Spectr Research Article In December 2019, a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started spreading worldwide causing the coronavirus disease 2019 (COVID-19) pandemic. The hyperactivation of the immune system has been proposed to account for disease severity and death in COVID-19 patients. Despite several approaches having been tested, no therapeutic protocol has been approved. Given that Cyclosporine A (CsA) is well-known to exert a strong antiviral activity on several viral strains and an anti-inflammatory role in different organs with relevant benefits in diverse pathological contexts, we tested its effects on SARS-CoV-2 infection of lung cells. We found that treatment with CsA either before or after infection of CaLu3 cells by three SARS-CoV-2 variants: (i) reduces the expression of both viral RNA and proteins in infected cells; (ii) decreases the number of progeny virions released by infected cells; (iii) dampens the virus-triggered synthesis of cytokines (including IL-6, IL-8, IL1α and TNF-α) that are involved in cytokine storm in patients. Altogether, these data provide a rationale for CsA repositioning for the treatment of severe COVID-19 patients. IMPORTANCE SARS-CoV-2 is the most recently identified member of the betacoronavirus genus responsible for the COVID-19 pandemic. Repurposing of available drugs has been a “quick and dirty” approach to try to reduce mortality and severe symptoms in affected patients initially, and can still represent an undeniable and valuable approach to face COVID-19 as the continuous appearance and rapid diffusion of more “aggressive”/transmissible variants, capable of eluding antibody neutralization, challenges the effectiveness of some anti-SARS-CoV-2 vaccines. Here, we tested a known antiviral and anti-inflammatory drug, Cyclosporine A (CsA), and found that it dampens viral infection and cytokine release from lung cells upon exposure to three different SARS-CoV-2 variants. Knock down of the main intracellular target of CsA, Cyclophilin A, does not phenocopy the drug inhibition of viral infection. Altogether, these findings shed new light on the cellular mechanisms of SARS-CoV-2 infection and provide the rationale for CsA repositioning to treat severe COVID-19 patients. American Society for Microbiology 2022-01-05 /pmc/articles/PMC8729790/ /pubmed/34985303 http://dx.doi.org/10.1128/spectrum.01504-21 Text en Copyright © 2022 Fenizia et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Fenizia, Claudio
Galbiati, Silvia
Vanetti, Claudia
Vago, Riccardo
Clerici, Mario
Tacchetti, Carlo
Daniele, Tiziana
Cyclosporine A Inhibits Viral Infection and Release as Well as Cytokine Production in Lung Cells by Three SARS-CoV-2 Variants
title Cyclosporine A Inhibits Viral Infection and Release as Well as Cytokine Production in Lung Cells by Three SARS-CoV-2 Variants
title_full Cyclosporine A Inhibits Viral Infection and Release as Well as Cytokine Production in Lung Cells by Three SARS-CoV-2 Variants
title_fullStr Cyclosporine A Inhibits Viral Infection and Release as Well as Cytokine Production in Lung Cells by Three SARS-CoV-2 Variants
title_full_unstemmed Cyclosporine A Inhibits Viral Infection and Release as Well as Cytokine Production in Lung Cells by Three SARS-CoV-2 Variants
title_short Cyclosporine A Inhibits Viral Infection and Release as Well as Cytokine Production in Lung Cells by Three SARS-CoV-2 Variants
title_sort cyclosporine a inhibits viral infection and release as well as cytokine production in lung cells by three sars-cov-2 variants
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8729790/
https://www.ncbi.nlm.nih.gov/pubmed/34985303
http://dx.doi.org/10.1128/spectrum.01504-21
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