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.
【저자키워드】 COVID-19, Ivermectin, Drug repurposing, SARS-CoV-2, antihelmintic drug, lipophilic statin, host cell antiviral response, atorvastatin, 【초록키워드】 Ivermectin, Treatment, Pathogenesis, Gene Expression, SARS-COV-2 infection, Infection, drugs, drug, Nasopharyngeal swab, Viral, nasopharyngeal swabs, RNA viruses, Patient, drug target, atorvastatin, distribution, expression, mechanism, function, COVID-19 patients, NF-κB, cellular, Signaling, Combination, COVID-19 patient, poly(I:C), host cells, host cell, confocal microscopy, Transport, Non-COVID-19 patients, alteration, NF-κB activation, Importin, Nuclear localization, Actin, Cdc42, Rho GTPase, in vitro model, KPNA3, KPNA5, KPNA7, KPNB1, nuclear, Rho GTPases, RHOA, viral double-stranded RNA, Effect, Affect, Vesicle, concentrations, transcriptional, Result, analyzed, involved, inhibit, cytoplasmic, triggered, impair, pleiotropic effect, 【제목키워드】 Ivermectin, drug, atorvastatin, target, Localization, Profiling, Effect,