Host factors regulating coronavirus infection
SARS-CoV-2 is the viral agent responsible for the COVID-19 pandemic with serious morbidity and mortality. Therapeutic measures are desperately needed as this virus has infected communities across the globe and novel more transmissible and immunologically distinct variants emerge. Host factors that regulate SARS-CoV-2 replication represent candidate druggable targets with a high likelihood of having broad-spectrum activity across the coronavirus family and perhaps other positive-sense RNA virus families. Functional genetic approaches, including genome-wide CRISPR screens, have been very effective in identifying host factors that regulate viral replication. We performed CRISPR knockout and activation screens for SARS-CoV-2 and endemic human coronavirus (HCoV) OC43 and are now studying the mechanism by which specific host factors regulate human coronavirus replication. The long-term goal is to develop novel and rational antiviral strategies based on this mechanistic insight.
Two highly enriched genes in our knockout screens were EDC4 and XRN1, both of which play key roles in regulated host mRNA decay and localize to P-bodies. Based on the functions of EDC4 and XRN1 in host cells and in the life cycle of other RNA viruses, we hypothesize that the virus exploits this pathway either to cause global host mRNA degradation and consequent suppression of host immunity or aid in the formation of the HCoV replication and transcription complex. We are also testing specific inhibitors of these host factors for antiviral activity.