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Differential interferon-α subtype induced immune signatures are associated with suppression of SARS-CoV-2 infection.
Proc Natl Acad Sci U S A. 2022 02 22; 119(8)PN

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 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 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.

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Authors+Show Affiliations

Schuhenn J
Institute for Virology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
Meister TL
Molecular and Medical Virology, Ruhr-University Bochum, 44801 Bochum, Germany.
Todt D
Molecular and Medical Virology, Ruhr-University Bochum, 44801 Bochum, Germany. European Virus Bioinformatics Center (EVBC), 07743 Jena, Germany.
Bracht T
Medical Proteome Center, Ruhr-University Bochum, 44801 Bochum, Germany. Department of Anesthesia, Intensive Care Medicine and Pain Therapy, University Hospital Knappschaftskrankenhaus Bochum, 44892 Bochum, Germany.
Schork K
Medical Proteome Center, Ruhr-University Bochum, 44801 Bochum, Germany. Center for Protein Diagnostics, Medical Proteome Analysis, Ruhr-University Bochum, 44801 Bochum, Germany.
Billaud JN
Qiagen Digital Insights, Redwood City, CA 94063.
Elsner C
Institute for Virology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
Heinen N
Molecular and Medical Virology, Ruhr-University Bochum, 44801 Bochum, Germany.
Karakoese Z
Institute for Virology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
Haid S
Department of Experimental Virology, Twincore, 30625 Hannover, Germany.
Kumar S
Institute of Virology Muenster, Westfaelische Wilhelms-University, 48149 Muenster, Germany.
Brunotte L
Institute of Virology Muenster, Westfaelische Wilhelms-University, 48149 Muenster, Germany. Interdisciplinary Centre for Clinical Research, University of Muenster, 48149 Muenster, Germany.
Eisenacher M
Medical Proteome Center, Ruhr-University Bochum, 44801 Bochum, Germany. Center for Protein Diagnostics, Medical Proteome Analysis, Ruhr-University Bochum, 44801 Bochum, Germany.
Di Y
Department of Biochemistry, Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Lew J
Vaccine and Infectious Disease Organization-International Vaccine Centre, University of Saskatchewan, Saskatoon, SK S7N 5E3, Canada.
Falzarano D
Vaccine and Infectious Disease Organization-International Vaccine Centre, University of Saskatchewan, Saskatoon, SK S7N 5E3, Canada.
Chen J
Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200433, China.
Yuan Z
Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200433, China.
Pietschmann T
Department of Experimental Virology, Twincore, 30625 Hannover, Germany. Cluster of Excellence RESIST, Hannover Medical School, 30625 Hannover, Germany. German Center for Infection Research, Partner Site Hannover-Braunschweig, 30625 Hannover, Germany.
Wiegmann B
Department for Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany.
Uebner H
Department of Pulmonary Medicine, Experimental Pneumology, University Medical Center Essen - Ruhrlandklinik, 45239 Essen, Germany.
Taube C
Department of Pulmonary Medicine, Experimental Pneumology, University Medical Center Essen - Ruhrlandklinik, 45239 Essen, Germany.
Le-Trilling VTK
Institute for Virology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
Trilling M
Institute for Virology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
Krawczyk A
Institute for Virology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. Department of Infectious Diseases, West German Centre of Infectious Diseases, University Hospital Essen, 45122 Essen, Germany.
Ludwig S
Institute of Virology Muenster, Westfaelische Wilhelms-University, 48149 Muenster, Germany. Interdisciplinary Centre for Clinical Research, University of Muenster, 48149 Muenster, Germany.
Sitek B
Medical Proteome Center, Ruhr-University Bochum, 44801 Bochum, Germany. Department of Anesthesia, Intensive Care Medicine and Pain Therapy, University Hospital Knappschaftskrankenhaus Bochum, 44892 Bochum, Germany.
Steinmann E
Molecular and Medical Virology, Ruhr-University Bochum, 44801 Bochum, Germany.
Dittmer U
Institute for Virology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
Lavender KJ
Department of Biochemistry, Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; kerry.lavender@usask.ca Kathrin.sutter@uni-due.de Stephanie.pfaender@rub.de.
Sutter K
Institute for Virology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany; kerry.lavender@usask.ca Kathrin.sutter@uni-due.de Stephanie.pfaender@rub.de.
Pfaender S
Molecular and Medical Virology, Ruhr-University Bochum, 44801 Bochum, Germany; kerry.lavender@usask.ca Kathrin.sutter@uni-due.de Stephanie.pfaender@rub.de.

MeSH

AnimalsCOVID-19Chlorocebus aethiopsCloning, MolecularDisease Models, AnimalEscherichia coliGene Expression ProfilingGene Expression RegulationGenetic VectorsHumansInterferon-alphaMiceProtein IsoformsRecombinant ProteinsSARS-CoV-2Signal TransductionTranscriptomeVero CellsVirus ReplicationCOVID-19 Drug Treatment

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

35131898

Citation

Schuhenn, Jonas, et al. "Differential Interferon-α Subtype Induced Immune Signatures Are Associated With Suppression of SARS-CoV-2 Infection." Proceedings of the National Academy of Sciences of the United States of America, vol. 119, no. 8, 2022.
Schuhenn J, Meister TL, Todt D, et al. Differential interferon-α subtype induced immune signatures are associated with suppression of SARS-CoV-2 infection. Proc Natl Acad Sci U S A. 2022;119(8).
Schuhenn, J., Meister, T. L., Todt, D., Bracht, T., Schork, K., Billaud, J. N., Elsner, C., Heinen, N., Karakoese, Z., Haid, S., Kumar, S., Brunotte, L., Eisenacher, M., Di, Y., Lew, J., Falzarano, D., Chen, J., Yuan, Z., Pietschmann, T., ... Pfaender, S. (2022). Differential interferon-α subtype induced immune signatures are associated with suppression of SARS-CoV-2 infection. Proceedings of the National Academy of Sciences of the United States of America, 119(8). https://doi.org/10.1073/pnas.2111600119
Schuhenn J, et al. Differential Interferon-α Subtype Induced Immune Signatures Are Associated With Suppression of SARS-CoV-2 Infection. Proc Natl Acad Sci U S A. 2022 02 22;119(8) PubMed PMID: 35131898.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential interferon-α subtype induced immune signatures are associated with suppression of SARS-CoV-2 infection. AU - Schuhenn,Jonas, AU - Meister,Toni Luise, AU - Todt,Daniel, AU - Bracht,Thilo, AU - Schork,Karin, AU - Billaud,Jean-Noel, AU - Elsner,Carina, AU - Heinen,Natalie, AU - Karakoese,Zehra, AU - Haid,Sibylle, AU - Kumar,Sriram, AU - Brunotte,Linda, AU - Eisenacher,Martin, AU - Di,Yunyun, AU - Lew,Jocelyne, AU - Falzarano,Darryl, AU - Chen,Jieliang, AU - Yuan,Zhenghong, AU - Pietschmann,Thomas, AU - Wiegmann,Bettina, AU - Uebner,Hendrik, AU - Taube,Christian, AU - Le-Trilling,Vu Thuy Khanh, AU - Trilling,Mirko, AU - Krawczyk,Adalbert, AU - Ludwig,Stephan, AU - Sitek,Barbara, AU - Steinmann,Eike, AU - Dittmer,Ulf, AU - Lavender,Kerry J, AU - Sutter,Kathrin, AU - Pfaender,Stephanie, PY - 2021/12/20/accepted PY - 2022/2/8/entrez PY - 2022/2/9/pubmed PY - 2022/2/19/medline KW - SARS-CoV-2 KW - antiviral KW - immunotherapy KW - type I IFNs JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 119 IS - 8 N2 - 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 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 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. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/35131898/Differential_interferon_α_subtype_induced_immune_signatures_are_associated_with_suppression_of_SARS_CoV_2_infection_ DB - PRIME DP - Unbound Medicine ER -