Résumé
Acknowledgements: This work was supported by the Agence Nationale de la Recherche (ANR-21-CE15-0041, to S.N. and Y.S., ANR-17-CE15-0029 to E.D., and ANR-20-CE11-0024 to E.D. and N.J.), the UK Medical Research Council (MC_UU_12014/10, MR/K024752/1 and MR/P022642/1 to S.J.W.) and the Foundation for Medical Research (FRM-REPLI80C/U160, FDT202204014965 to E.D.). J.Z. was supported by a grant from the Agence Nationale de la Recherche (ANR-21-CE15-0041-03). M.C. and I.B. are recipients of doctoral grants from the French Ministry of Higher Education and Research. We acknowledge the imaging facility of Montpellier (MRI), member of the national infrastructure France-BioImaging supported by the Agence Nationale de la Recherche (ANR-10-INBS-04, “Investissements d′avenir”). This publication was supported by the European Virus Archive GLOBAL (EVA-GLOBAL) project that has received funding from the European Union′s Horizon 2020 research and innovation program under grant agreement No 871029. We thank Karim Majzoub and Pierre Khalfi (IGMM, Montpellier, France) for helpful discussions and Nathalie J. Arhel (IRIM, Montpellier, France) for critical reading of the manuscript.
Usutu virus (USUV) and West Nile virus (WNV) are two closely related emerging mosquito-borne flaviviruses. Their natural hosts are wild birds, but they can also cause severe neurological disorders in humans. Both viruses are efficiently suppressed by type I interferon (IFN), which interferes with viral replication, dissemination, pathogenesis and transmission. Here, we show that the replication of USUV and WNV are inhibited through a common set of IFN-induced genes (ISGs), with the notable exception of ISG20, which USUV is resistant to. Strikingly, USUV was the only virus among all the other tested mosquito-borne flaviviruses that demonstrated resistance to the 3'-5' exonuclease activity of ISG20. Our findings highlight that the intrinsic resistance of the USUV genome, irrespective of the presence of cellular or viral proteins or protective post-transcriptional modifications, relies on a unique sequence present in its 3' untranslated region. Importantly, this genomic region alone can confer ISG20 resistance to a susceptible flavivirus, without compromising its infectivity, suggesting that it could be acquired by other flaviviruses. This study provides new insights into the strategy employed by emerging flaviviruses to overcome host defense mechanisms.