A resource of human coronavirus protein-coding sequences in a flexible, multipurpose Gateway Entry clone collection.

The COVID-19 pandemic has catalyzed unprecedented scientific data and reagent sharing and collaboration, which enabled understanding the virology of the SARS-CoV-2 virus and vaccine development at record speed. The pandemic, however, has also raised awareness of the danger posed by the family of coronaviruses, of which 7 are known to infect humans and dozens have been identified in reservoir species, such as bats, rodents, or livestock. To facilitate understanding the commonalities and specifics of coronavirus infections and aspects of viral biology that determine their level of lethality to the human host, we have generated a collection of freely available clones encoding nearly all human coronavirus proteins known to date. We hope that this flexible, Gateway-compatible vector collection will encourage further research into the interactions of coronaviruses with their human host, to increase preparedness for future zoonotic viral outbreaks.

A proteome-scale map of the SARS-CoV-2-human contactome.

Understanding the mechanisms of coronavirus disease 2019 (COVID-19) disease severity to efficiently design therapies for emerging virus variants remains an urgent challenge of the ongoing pandemic. Infection and immune reactions are mediated by direct contacts between viral molecules and the host proteome, and the vast majority of these virus-host contacts (the 'contactome') have not been identified. Here, we present a systematic contactome map of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with the human host encompassing more than 200 binary virus-host and intraviral protein-protein interactions. We find that host proteins genetically associated with comorbidities of severe illness and long COVID are enriched in SARS-CoV-2 targeted network communities. Evaluating contactome-derived hypotheses, we demonstrate that viral NSP14 activates nuclear factor κB (NF-κB)-dependent transcription, even in the presence of cytokine signaling. Moreover, for several tested host proteins, genetic knock-down substantially reduces viral replication. Additionally, we show for USP25 that this effect is phenocopied by the small-molecule inhibitor AZ1. Our results connect viral proteins to human genetic architecture for COVID-19 severity and offer potential therapeutic targets.