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

• Published in: Viruses Vol. 13; no. 10; p. 2084
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 15.10.2021; MDPI
• Subjects: A549 Cells; Actin; Actin Cytoskeleton - drug effects; Active Transport, Cell Nucleus - drug effects; alpha Karyopherins - metabolism; Animals; Antibiotics; Antibodies; antihelmintic drug; Antiviral Agents - pharmacology; Atorvastatin; Atorvastatin - pharmacology; Cdc42 protein; Cell Line, Tumor; Chlorocebus aethiops; Confocal microscopy; Coronaviruses; COVID-19; COVID-19 Drug Treatment; Cytoskeleton; Datasets; Double-stranded RNA; Drug dosages; Drug Repositioning; drug repurposing; Gene amplification; Gene expression; Guanosine triphosphatases; HeLa Cells; host cell antiviral response; Humans; Infections; Ivermectin; Ivermectin - pharmacology; lipophilic statin; Localization; Manufacturers; Microscopy; NF-kappa B - metabolism; NF-κB protein; Nuclear transport; Pandemics; Patients; Poly (I:C); rho GTP-Binding Proteins - metabolism; RhoA protein; RNA viruses; SARS-CoV-2; SARS-CoV-2 - drug effects; Severe acute respiratory syndrome coronavirus 2; Therapeutic targets; Transcription; Vero Cells; United Kingdom > UK; United States > US; Argentina; COVID-19; lipophilic statin; SARS-CoV-2; drug repurposing; host cell antiviral response; atorvastatin; ivermectin; antihelmintic drug
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v13102084

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.