Transcriptomics-inferred dynamics of SARS-CoV-2 interactions with host epithelial cells

Virus-host interactions can reveal potentially effective and selective therapeutic targets for treating infection. Here, we performed an integrated analysis of the dynamics of virus replication and the host cell transcriptional response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using human Caco-2 colon cancer cells as a model. Time-resolved RNA sequencing revealed that, upon infection, cells immediately transcriptionally activated genes associated with inflammatory pathways that mediate the antiviral response, which was followed by an increase in the expression of genes involved in ribosome and mitochondria function, thus suggesting rapid alterations in protein production and cellular energy supply. At later stages, between 24 and 48 hours after infection, the expression of genes involved in metabolic processes—in particular, those related to xenobiotic metabolism—was decreased. Mathematical modeling incorporating SARS-CoV-2 replication suggested that SARS-CoV-2 proteins inhibited the host antiviral response and that virus transcripts exceeded the translation capacity of the host cells. Targeting kinase-dependent pathways that exhibited increases in transcription in host cells was as effective as a virus-targeted inhibitor at repressing viral replication. Our findings in this model system delineate a sequence of SARS-CoV-2 virus-host interactions that may facilitate the identification of druggable host pathways to suppress infection. The timing of transcriptional events in SARS-CoV-2–infected cells reveals a host-targeted treatment. SARS-CoV-2 is adept at evading both virus-targeted drugs and host immune responses. Targeting the proteins and processes in host cells that support the infection is an alternative approach. Adam et al . devised a model of transcriptional dynamics in host epithelial cells from the moment of infection with SARS-CoV-2 to the point of cell lysis. The model suggested that RNA and protein synthesis machineries in host cells, which mediate an initial antiviral response, are quickly co-opted by the virus to support its replication. Viral propagation in cell culture was effectively suppressed by sorafenib, a clinically approved drug that targets several host cell pathways implicated in the model to support viral replication. —Leslie K. Ferrarelli