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Systematic analysis of innate immune antagonism reveals vulnerabilities of SARS-CoV-2

View ORCID ProfileManuel Hayn, View ORCID ProfileMaximilian Hirschenberger, View ORCID ProfileLennart Koepke, Jan H Straub, Rayhane Nchioua, Susanne Klute, Caterina Prelli Bozzo, Wasim Aftab, View ORCID ProfileFabian Zech, Carina Conzelmann, Janis A Müller, Smitha Srinivasachar Badarinarayan, Christina M Stürzel, Ignasi Forne, Steffen Stenger, Karl-Klaus Conzelmann, Jan Münch, View ORCID ProfileDaniel Sauter, View ORCID ProfileAxel Imhof, View ORCID ProfileFrank Kirchhoff, View ORCID ProfileKonstantin MJ Sparrer
doi: https://doi.org/10.1101/2020.10.15.340612
Manuel Hayn
1Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
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Maximilian Hirschenberger
1Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
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  • ORCID record for Maximilian Hirschenberger
Lennart Koepke
1Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
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Jan H Straub
1Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
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Rayhane Nchioua
1Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
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Susanne Klute
1Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
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Caterina Prelli Bozzo
1Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
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Wasim Aftab
3Biomedical Center, Zentrallabor für Proteinanalytik (Protein Analysis Unit), Department of Molecular Biology, Ludwig-Maximilians-University of Munich, 82152 Planegg-Martinsried, Germany
4Graduate School for Quantitative Biosciences (QBM), Ludwig-Maximilians-University of Munich, 81377 Munich, Germany
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Fabian Zech
1Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
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Carina Conzelmann
1Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
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Janis A Müller
1Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
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Smitha Srinivasachar Badarinarayan
1Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
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Christina M Stürzel
1Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
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Ignasi Forne
3Biomedical Center, Zentrallabor für Proteinanalytik (Protein Analysis Unit), Department of Molecular Biology, Ludwig-Maximilians-University of Munich, 82152 Planegg-Martinsried, Germany
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Steffen Stenger
5Institute for Medical Microbiology and Hygiene, Ulm University Medical Center, 89081 Ulm, Germany
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Karl-Klaus Conzelmann
2Gene Center & Max von Pettenkofer-Institute of Virology, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany
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Jan Münch
1Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
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Daniel Sauter
1Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
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Axel Imhof
3Biomedical Center, Zentrallabor für Proteinanalytik (Protein Analysis Unit), Department of Molecular Biology, Ludwig-Maximilians-University of Munich, 82152 Planegg-Martinsried, Germany
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Frank Kirchhoff
1Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
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Konstantin MJ Sparrer
1Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
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  • ORCID record for Konstantin MJ Sparrer
  • For correspondence: Konstantin.Sparrer@uni-ulm.de
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ABSTRACT

The innate immune system efficiently defends the human host against viral pathogens. Thus, viruses evolved strategies to counteract immune activation. Here, we systematically analysed the impact of 29 SARS-CoV-2 encoded proteins on three major arms of our cell-intrinsic innate immune defences: interferon (IFN) induction, cytokine signalling and autophagy. Subsequent mechanistic analyses revealed that SARS-CoV-2 proteins target the respective signalling cascades at multiple steps. For example, we show that Nsp14 reduces endogenous IFN receptor levels and ORF3a and ORF7a perturb the late endosomal/trans-Golgi network. Our data demonstrates that most antagonistic activities are conserved between proteins encoded by SARS-CoV-2, the closely related bat RaTG13-CoV and the highly pathogenic SARS-CoV-1. However, SARS-CoV-1 Nsp15 is strikingly more potent in suppressing IFN induction and signalling than its SARS-CoV-2 counterpart. This may help explain the lower pathogenicity of SARS-CoV-2, which facilitated its rapid spread. Overall our analyses revealed that IFN-γ and IFN-λ1 signalling are antagonised the least, leaving SARS-CoV-2 highly susceptible to these two cytokines. Their combination synergistically potentiated the anti-viral effects against SARS-CoV-2 at low concentrations. Taken together, our results allow an explanation for differences in susceptibility towards IFNs and provide evidence that rational immune activation may be an effective future therapeutic strategy against SARS-CoV-2.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 15, 2020.
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Systematic analysis of innate immune antagonism reveals vulnerabilities of SARS-CoV-2
Manuel Hayn, Maximilian Hirschenberger, Lennart Koepke, Jan H Straub, Rayhane Nchioua, Susanne Klute, Caterina Prelli Bozzo, Wasim Aftab, Fabian Zech, Carina Conzelmann, Janis A Müller, Smitha Srinivasachar Badarinarayan, Christina M Stürzel, Ignasi Forne, Steffen Stenger, Karl-Klaus Conzelmann, Jan Münch, Daniel Sauter, Axel Imhof, Frank Kirchhoff, Konstantin MJ Sparrer
bioRxiv 2020.10.15.340612; doi: https://doi.org/10.1101/2020.10.15.340612
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Systematic analysis of innate immune antagonism reveals vulnerabilities of SARS-CoV-2
Manuel Hayn, Maximilian Hirschenberger, Lennart Koepke, Jan H Straub, Rayhane Nchioua, Susanne Klute, Caterina Prelli Bozzo, Wasim Aftab, Fabian Zech, Carina Conzelmann, Janis A Müller, Smitha Srinivasachar Badarinarayan, Christina M Stürzel, Ignasi Forne, Steffen Stenger, Karl-Klaus Conzelmann, Jan Münch, Daniel Sauter, Axel Imhof, Frank Kirchhoff, Konstantin MJ Sparrer
bioRxiv 2020.10.15.340612; doi: https://doi.org/10.1101/2020.10.15.340612

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