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Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients

Nuclear transport and vesicle trafficking are key cellular functions involved in the pathogenesis of RNA viruses. Among other pleiotropic effects on virus-infected host cells, ivermectin (IVM) inhibits nuclear transport mechanisms mediated by importins and atorvastatin (ATV) affects actin cytoskelet...

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Autores principales: Segatori, Valeria Inés, Garona, Juan, Caligiuri, Lorena Grisel, Bizzotto, Juan, Lavignolle, Rosario, Toro, Ayelén, Sanchis, Pablo, Spitzer, Eduardo, Krolewiecki, Alejandro, Gueron, Geraldine, Alonso, Daniel Fernando
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537229/
https://www.ncbi.nlm.nih.gov/pubmed/34696514
http://dx.doi.org/10.3390/v13102084
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author Segatori, Valeria Inés
Garona, Juan
Caligiuri, Lorena Grisel
Bizzotto, Juan
Lavignolle, Rosario
Toro, Ayelén
Sanchis, Pablo
Spitzer, Eduardo
Krolewiecki, Alejandro
Gueron, Geraldine
Alonso, Daniel Fernando
author_facet Segatori, Valeria Inés
Garona, Juan
Caligiuri, Lorena Grisel
Bizzotto, Juan
Lavignolle, Rosario
Toro, Ayelén
Sanchis, Pablo
Spitzer, Eduardo
Krolewiecki, Alejandro
Gueron, Geraldine
Alonso, Daniel Fernando
author_sort Segatori, Valeria Inés
collection PubMed
description Nuclear transport and vesicle trafficking are key cellular functions involved in the pathogenesis of RNA viruses. Among other pleiotropic effects on virus-infected host cells, ivermectin (IVM) inhibits nuclear transport mechanisms mediated by importins and atorvastatin (ATV) affects actin cytoskeleton-dependent trafficking controlled by Rho GTPases signaling. In this work, we first analyzed the response to infection in nasopharyngeal swabs from SARS-CoV-2-positive and -negative patients by assessing the gene expression of the respective host cell drug targets importins and Rho GTPases. COVID-19 patients showed alterations in KPNA3, KPNA5, KPNA7, KPNB1, RHOA, and CDC42 expression compared with non-COVID-19 patients. An in vitro model of infection with Poly(I:C), a synthetic analog of viral double-stranded RNA, triggered NF-κB activation, an effect that was halted by IVM and ATV treatment. Importin and Rho GTPases gene expression was also impaired by these drugs. Furthermore, through confocal microscopy, we analyzed the effects of IVM and ATV on nuclear to cytoplasmic importin α distribution, alone or in combination. Results showed a significant inhibition of importin α nuclear accumulation under IVM and ATV treatments. These findings confirm transcriptional alterations in importins and Rho GTPases upon SARS-CoV-2 infection and point to IVM and ATV as valid drugs to impair nuclear localization of importin α when used at clinically-relevant concentrations.
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spelling pubmed-85372292021-10-24 Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients Segatori, Valeria Inés Garona, Juan Caligiuri, Lorena Grisel Bizzotto, Juan Lavignolle, Rosario Toro, Ayelén Sanchis, Pablo Spitzer, Eduardo Krolewiecki, Alejandro Gueron, Geraldine Alonso, Daniel Fernando Viruses Article Nuclear transport and vesicle trafficking are key cellular functions involved in the pathogenesis of RNA viruses. Among other pleiotropic effects on virus-infected host cells, ivermectin (IVM) inhibits nuclear transport mechanisms mediated by importins and atorvastatin (ATV) affects actin cytoskeleton-dependent trafficking controlled by Rho GTPases signaling. In this work, we first analyzed the response to infection in nasopharyngeal swabs from SARS-CoV-2-positive and -negative patients by assessing the gene expression of the respective host cell drug targets importins and Rho GTPases. COVID-19 patients showed alterations in KPNA3, KPNA5, KPNA7, KPNB1, RHOA, and CDC42 expression compared with non-COVID-19 patients. An in vitro model of infection with Poly(I:C), a synthetic analog of viral double-stranded RNA, triggered NF-κB activation, an effect that was halted by IVM and ATV treatment. Importin and Rho GTPases gene expression was also impaired by these drugs. Furthermore, through confocal microscopy, we analyzed the effects of IVM and ATV on nuclear to cytoplasmic importin α distribution, alone or in combination. Results showed a significant inhibition of importin α nuclear accumulation under IVM and ATV treatments. These findings confirm transcriptional alterations in importins and Rho GTPases upon SARS-CoV-2 infection and point to IVM and ATV as valid drugs to impair nuclear localization of importin α when used at clinically-relevant concentrations. MDPI 2021-10-15 /pmc/articles/PMC8537229/ /pubmed/34696514 http://dx.doi.org/10.3390/v13102084 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Segatori, Valeria Inés
Garona, Juan
Caligiuri, Lorena Grisel
Bizzotto, Juan
Lavignolle, Rosario
Toro, Ayelén
Sanchis, Pablo
Spitzer, Eduardo
Krolewiecki, Alejandro
Gueron, Geraldine
Alonso, Daniel Fernando
Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients
title Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients
title_full Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients
title_fullStr Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients
title_full_unstemmed Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients
title_short Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients
title_sort effect of ivermectin and atorvastatin on nuclear localization of importin alpha and drug target expression profiling in host cells from nasopharyngeal swabs of sars-cov-2- positive patients
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537229/
https://www.ncbi.nlm.nih.gov/pubmed/34696514
http://dx.doi.org/10.3390/v13102084
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