RESUMEN
Understanding pathways that might impact coronavirus disease 2019 (COVID-19) manifestations and disease outcomes is necessary for better disease management and for therapeutic development. Here, we analyzed alterations in sphingolipid (SL) levels upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection induced elevation of SL levels in both cells and sera of infected mice. A significant increase in glycosphingolipid levels was induced early post SARS-CoV-2 infection, which was essential for viral replication. This elevation could be reversed by treatment with glucosylceramide synthase inhibitors. Levels of sphinganine, sphingosine, GA1, and GM3 were significantly increased in both cells and the murine model upon SARS-CoV-2 infection. The potential involvement of SLs in COVID-19 pathology is discussed.
Asunto(s)
COVID-19/metabolismo , Modelos Animales de Enfermedad , Esfingolípidos/metabolismo , Replicación Viral/fisiología , Animales , COVID-19/prevención & control , COVID-19/virología , Chlorocebus aethiops , Cromatografía Liquida/métodos , Dioxanos/farmacología , Gangliósidos/sangre , Gangliósidos/metabolismo , Glucosiltransferasas/antagonistas & inhibidores , Glucosiltransferasas/metabolismo , Humanos , Espectrometría de Masas/métodos , Ratones Transgénicos , Pirrolidinas/farmacología , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/fisiología , Esfingolípidos/sangre , Esfingosina/análogos & derivados , Esfingosina/sangre , Esfingosina/metabolismo , Células Vero , Replicación Viral/efectos de los fármacosRESUMEN
The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major threat to global health. Vaccines are ideal solutions to prevent infection, but treatments are also needed for those who have contracted the virus to limit negative outcomes, when vaccines are not applicable. Viruses must cross host cell membranes during their life cycle, creating a dependency on processes involving membrane dynamics. Thus, in this study, we examined whether the synthetic machinery for glycosphingolipids, biologically active components of cell membranes, can serve as a therapeutic target to combat SARS-CoV-2. We examined the antiviral effect of two specific inhibitors of glucosylceramide synthase (GCS): (i) Genz-123346, an analogue of the United States Food and Drug Administration-approved drug Cerdelga and (ii) GENZ-667161, an analogue of venglustat, which is currently under phase III clinical trials. We found that both GCS inhibitors inhibit replication of SARS-CoV-2. Moreover, these inhibitors also disrupt replication of influenza virus A/PR/8/34 (H1N1). Our data imply that synthesis of glycosphingolipids is necessary to support viral life cycles and suggest that GCS inhibitors should be further explored as antiviral therapies.