Sequence and dynamics of SARS-CoV-2 host cell interactions inferred from transcriptome analyses

The worldwide spread of severe acute respiratory syndrome-related coronavirus-2 (SARS- CoV-2) caused an urgent need for an in-depth understanding of virus-host interactions. Here, we dissected the dynamics of virus replication and the host cell transcriptional response to SARS-CoV-2 infection at a systems level by combining time-resolved RNA sequencing with mathematical modeling. We observed an immediate transcriptional activation of inflammatory pathways linked to the anti-viral response followed by increased expression of genes involved in ribosome and mitochondria function, thus hinting at rapid alterations in protein production and cellular energy supply. At later stages, metabolic processes, in particular those related to xenobiotic metabolism, were downregulated. To gain a deeper understanding of the underlying transcriptional dynamics, we developed an ODE model of SARS-CoV-2 infection and replication. Mathematical modeling of SARS-CoV-2 replication suggested a strong inhibitory effect of SARS-CoV-2 proteins on the anti-viral response and a large excess of virus transcripts over the translation capacity. Our study provides insights into the sequence of SARS-CoV-2 virus-host interactions and facilitates the identification of druggable host pathways supporting virus replication. Overall design: RNA-sequencing of SARS-CoV-2 infected Caco-2 cells at different timepoints after viral infection (0h, 1h, 2h, 4h, 7h, 12h, 24h & 48h). Mock samples were used as control at t=4h,12h,48h. Replicates (n=3) were obtained for each time point