Role of Top1 and Genome structure in SARS-CoV-2 infection [RNA-Seq human]

The ongoing pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Targeting these pathways might therefore be a viable therapeutic strategy. Previously, we have reported that chromatin factors such as Topoisomerase I (Top1) play key roles in controlling the induction of inflammatory gene expression programs. Here, by using multidimensional epigenetic, transcriptional, in vitro and in vivo analyses, we show that Topoisomerase 1 (Top1) inhibition in infected cells and animals suppresses lethal inflammation induced by SARS-CoV-2. Overall design: To study alterations in genome structure after SARS-CoV-2 infection, we performed Hi-C on SARS-CoV-2 infected A549-ACE2 cells at 0,8 and 24 hours post infection. Experiment was done in biological duplicate. Each biological replicate was sequenced with 4 technical replicates. To study the impact of Top1 on the inflammatory response to SARS-CoV-2, we knocked-down TOP1 expression using siRNA in A549-ACE2 cells. Cells were then left uninfected or infected with SARS-CoV-2. Cells that were not treated with siRNA (no siRNA) or scrambled siRNA (siSCR) were used as controls. The experiment was done in triplicate.