National Center of Competence
in Research, RNA & Disease

Common host factors required for replication of coronaviruses identified

Enrichment map summarizing major host biological networks co-opted by coronaviruses during infection.

The Thiel lab, together with collaborators, conducted two genome-wide screens to identify host factors required by endemic and emerging coronaviruses. They discovered that both classes require several autophagy-related genes. Among them were members of the immunophilin family and they could show that their inhibition with drugs, including one that is non-immunosuppressive, reduces the replication of coronaviruses in a dose-dependent manner. Clinically approved drugs against these targets could potentially be used for the treatment of patients. Their findings were posted as a preprint entitled "A genome-wide CRISPR screen identifies interactors of the autophagy pathway as conserved coronavirus targets" on bioRxiv.

Abstract
Over the past 20 years, the emergence of three highly pathogenic coronaviruses (CoV) SARS-CoV, MERS-CoV, and most recently SARS-CoV-2 has shown that CoVs pose a serious risk to human health and highlighted the importance of developing effective therapies against them. Similar to other viruses, CoVs are dependent on host factors for their survival and replication. We hypothesized that evolutionarily distinct CoVs may exploit similar host factors and pathways to support their replication cycle. Here, we conducted two independent genome-wide CRISPR/Cas9 knockout screens to identify pan-CoV host factors required for the replication of both endemic and emerging CoVs, including the novel CoV SARS-CoV-2. Strikingly, we found that several autophagy-related genes, including the immunophilin FKBP8, TMEM41B, and MINAR1, were common host factors required for CoV replication. Importantly, inhibition of the immunophilin family with the compounds Tacrolimus, Cyclosporin A, and the non-immunosuppressive derivative Alisporivir, resulted in dose-dependent inhibition of CoV replication in primary human nasal epithelial cell cultures that resemble the natural site of virus replication. Overall, we identified host factors that are crucial for CoV replication and demonstrate that these factors constitute potential targets for therapeutic intervention by clinically approved drugs.

Read the Preprint on bioRxiv

Website Thiel lab

Abstract and Figure from Kratzel et al. (2021) bioRxiv published under a CC BY-ND 4.0 license.

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