TY - JOUR T1 - The Zinc Finger Antiviral Protein restricts SARS-CoV-2 JF - bioRxiv DO - 10.1101/2020.06.04.134379 SP - 2020.06.04.134379 AU - Rayhane Nchioua AU - Dorota Kmiec AU - Janis Müller AU - Carina Conzelmann AU - Rüdiger Groß AU - Chad Swanson AU - Stuart Neil AU - Steffen Stenger AU - Daniel Sauter AU - Jan Münch AU - Konstantin M. J. Sparrer AU - Frank Kirchhoff Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/06/04/2020.06.04.134379.abstract N2 - Recent evidence shows that the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is highly sensitive to interferons (IFNs). However, the underlying antiviral effectors remain to be defined. Here, we show that Zinc finger antiviral protein (ZAP) that specifically targets CpG dinucleotides in viral RNA sequences restricts SARS-CoV-2. We demonstrate that ZAP and its cofactors KHNYN and TRIM25 are expressed in human lung cells. Type I, II and III IFNs all strongly inhibited SARS-CoV-2 and further induced ZAP expression. Strikingly, SARS-CoV-2 and its closest relatives from bats show the strongest CpG suppression among all known human and bat coronaviruses, respectively. Nevertheless, knock-down of ZAP significantly increased SARS-CoV-2 production in lung cells, particularly upon treatment with IFN-α or IFN-γ. Thus, our results identify ZAP as an effector of the IFN response against SARS-CoV-2, although this pandemic pathogen may be preadapted to the low CpG environment in humans.HighlightsSARS-CoV-2 and its closest bat relatives show strong CpG suppressionIFN-β, -γ and -λ inhibit SARS-CoV-2 with high efficiencyZAP restricts SARS-CoV-2 and contributes to the antiviral effect of IFNsCompeting Interest StatementThe authors have declared no competing interest. ER -