Clash of the titans: RNA viruses and interferons

The interferon (IFN) response is a critical arm of the innate immune response and a major host defense mechanism against viral infections. Numerous genes that contribute to this antiviral state remain to be identified and characterized. Using large-scale loss-of-function strategies, we screened siRNAs or gRNAs libraries targeting hundreds of IFN-stimulated genes (ISGs) in IFN-treated cells infected with human RNA viruses, including coronaviruses and flaviviruses. We recovered previously unrecognized human genes able to modulate the replication these RNA viruses in an IFN-dependent manner. For instance, we identified DAXX, a scaffold protein residing in PML nuclear bodies, as a potent SARS-CoV-2 specific antiviral factor and MTA2, a chromatin remodeling protein, as a factor inhibiting flavivirus replication. We are also expanding our studies to the identification and characterization of ISGs in animal species that serve as viral reservoirs, such as bats. Finally, we are studying the mechanisms by which these viruses counteract the IFN response. For instance, through unbiased screening approaches, we recently uncovered a novel mechanism by which tick-borne flaviviruses antagonize IFN signaling. Our studies should open new perspectives to target weakness points in the life cycle of these emerging RNA viruses.

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