GSE178157
Niclosamide as a chemical probe for analyzing SARS-CoV-2 modulation of host cell lipid metabolism
Purpose: The global effort to combat COVID-19 rapidly produced a shortlist of approved drugs with anti-viral activities for clinical repurposing. However, the jump to clinical testing was lethal in some cases since a full understanding of the mechanism of antiviral activity as opposed to inherent toxicity for these drugs was lacking. We used parallel lipidomic and transcriptomic analyses to investigate the effect of Niclosamide (NIC), a poorly soluble anti-helminth drug identified for repurposed treatment of COVID-19, on SARS-CoV-2 infected Vero E6 cells. Methods: A time of addition study was performed on VeroE6 cells to gain mRNA profiles of 16 and 48h SARS-CoV-2 and/or niclosamide infected cells in triplicate, using an Illumina NovaSeq6000 platfrom. Sequence reads that passed quality filters were analyzed by featurecounts and DESeq2. Results: Herein, we identified and characterized autophagic or lipophagic pathways (and wider linked cellular networks) that are targeted by NIC in the presence and absence of a SARS-CoV-2 infection. We used the lipid and gene expression signatures induced by this anti-parasitic compound to detect pathways that are predicted to either lead to direct antiviral effects or to cellular dysregulation and cell death. Conclusions: NIC treatment reduced the abundance of phosphatidylethanolamines (PE), a known activator of autophagy, only after establishment of SARS-CoV-2 infection. Countering SARS-CoV-2 subversion of lipid metabolism by NIC through the activation of PE may lead to a focused screen for approved, more druggable compounds that can suppress viral replication in COVID-19 patients. Overall design: Vero E6 cell mRNA profiles at 0h, 16h or 48h treated and/or infected with NIC or SARS-CoV-2