Abstract
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 (α) 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 IFNα 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 IFNα subtypes during SARS-CoV-2 infection uncovered distinct functional classes with high, intermediate, and low antiviral IFNs. In particular, IFNα5 showed superior antiviral activity against SARS-CoV-2 infection invitro and in SARS-CoV-2-infected mice invivo. 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 IFNα 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 IFNα5. 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.
Highlights
Jonas Schuhenna,1, Toni Luise Meisterb,1, Daniel Todtb,c, Thilo Brachtd,e, Karin Schorkd,f, Jean-Noel Billaudg, Carina Elsnera, Natalie Heinenb, Zehra Karakoesea, Sibylle Haidh, Sriram Kumari, Linda Brunottei,j, Martin Eisenacherd,f, Yunyun Dik, Jocelyne Lewl, Darryl Falzaranol, Jieliang Chenm, Zhenghong Yuanm, Thomas Pietschmannh,n,o, Bettina Wiegmannp, Hendrik Uebnerq, Christian Taubeq, Vu Thuy Khanh Le-Trillinga, Mirko Trillinga, Adalbert Krawczyka,r, Stephan Ludwigi,j, Barbara Sitekd,e, Eike Steinmannb, Ulf Dittmera, Kerry J
Corroborating previous results, a striking clustering of the antiviral subtypes according to their antiviral potency was observed, which allowed their separation into classes of low (IC50 > 5,000 U/mL), intermediate (IC50 = 2,000 U/mL to 5,000 U/mL) and high (IC50 < 2,000 U/mL) antiviral activities against SARS-CoV-2 (Fig. 1 C–F and SI Appendix, Fig. S1 B–D and Table 1)
Defectiveness to IFN-I significantly contributes to disease severity, and genetic polymorphisms decreasing IFN-I production are associated with more severe cases of COVID-19 [44,45,46]
Summary
Jonas Schuhenna, , Toni Luise Meisterb,, Daniel Todtb,c, Thilo Brachtd,e, Karin Schorkd,f , Jean-Noel Billaudg , Carina Elsnera , Natalie Heinenb , Zehra Karakoesea, Sibylle Haidh , Sriram Kumari , Linda Brunottei,j , Martin Eisenacherd,f, Yunyun Dik , Jocelyne Lewl, Darryl Falzaranol , Jieliang Chenm, Zhenghong Yuanm, Thomas Pietschmannh,n,o , Bettina Wiegmannp, Hendrik Uebnerq, Christian Taubeq, Vu Thuy Khanh Le-Trillinga , Mirko Trillinga , Adalbert Krawczyka,r , Stephan Ludwigi,j , Barbara Sitekd,e, Eike Steinmannb, Ulf Dittmera, Kerry J. We comprehensively analyzed the antiviral activity of all IFNα subtypes against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to identify the underlying immune signatures and explore their therapeutic potential. We analyzed the antiviral activity of all human IFNα subtypes against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to identify the underlying immune signatures and explore their therapeutic potential. Given their large genome size, CoVs have evolved a variety of strategies circumventing the host innate immune reaction, including evasion strategies targeting IFN-I signaling [24, 26,27,28] Along those lines, recent studies showed significantly decreased IFN activity in COVID19 patients who developed more severe disease [29], highlighting the importance of IFN in controlling viral infection. The aim of this study was twofold: 1) to identify underlying immune signatures crucial for controlling SARS-CoV-2 infection and 2) to explore the therapeutic potential of IFNα subtypes in SARS-CoV-2 infection
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