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Jonas Schuhenn, Toni Luise Meister, Daniel Matthias Todt, Thilo Bracht, Karin Schork, Jean-Noel Billaud, Carina Elsner, Natalie Heinen, Zehra Karakoese, Sibylle Haid, Sriram Kumar, Linda Brunotte, Martin Eisenacher, Yunyun Di, Jocelyne Lew, Darryl Falzarano, Jieliang Chen, Zhenghong Yuan, Thomas Pietschmann, Bettina Pamela Wiegmann, Hendrik Übner, Christian Taube, Vu Thuy Khanh Le-Trilling, Mirko Trilling, Adalbert Krawczyk, Stephan Ludwig, Barbara Sitek, Eike Steinmann, Ulf Dittmer, Kerry J. Lavender, Kathrin Sutter, Stephanie Pfänder

• Type I interferons (IFN-I) exert pleiotropic biological effects during viral infections, balancing virus control versus immune-mediated pathologies, and have been successfully employed for the treatment of viral diseases. Humans express 12 IFN-alpha (\(\alpha\)) subtypes, which activate downstream signaling cascades and result in distinct patterns of immune responses and differential antiviral responses. Inborn errors in IFN-I immunity and the presence of anti-IFN autoantibodies account for very severe courses of COVID-19; therefore, early administration of IFN-I may be protective against life-threatening disease. Here we comprehensively analyzed the antiviral activity of all IFN\(\alpha\) subtypes against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to identify the underlying immune signatures and explore their therapeutic potential. Prophylaxis of primary human airway epithelial cells (hAEC) with different IFN\(\alpha\) subtypes during SARS-CoV-2 infection uncovered distinct functional classes with high, intermediate, and low antiviral IFNs. In particular, IFN\(\alpha\)5 showed superior antiviral activity against SARS-CoV-2 infection in vitro and in SARS-CoV-2–infected mice in vivo. Dose dependency studies further displayed additive effects upon coadministration with the broad antiviral drug remdesivir in cell culture. Transcriptomic analysis of IFN-treated hAEC revealed different transcriptional signatures, uncovering distinct, intersecting, and prototypical genes of individual IFN\(\alpha\) subtypes. Global proteomic analyses systematically assessed the abundance of specific antiviral key effector molecules which are involved in IFN-I signaling pathways, negative regulation of viral processes, and immune effector processes for the potent antiviral IFN\(\alpha\)5. Taken together, our data provide a systemic, multimodular definition of antiviral host responses mediated by defined IFN-I. This knowledge will support the development of novel therapeutic approaches against SARS-CoV-2.