Cell Reports (May 2021)
Systematic functional analysis of SARS-CoV-2 proteins uncovers viral innate immune antagonists and remaining vulnerabilities
- Manuel Hayn,
- Maximilian Hirschenberger,
- Lennart Koepke,
- Rayhane Nchioua,
- Jan Hendrik Straub,
- Susanne Klute,
- Victoria Hunszinger,
- Fabian Zech,
- Caterina Prelli Bozzo,
- Wasim Aftab,
- Maria Hønholt Christensen,
- Carina Conzelmann,
- Janis Alexander Müller,
- Smitha Srinivasachar Badarinarayan,
- Christina Martina Stürzel,
- Ignasi Forne,
- Steffen Stenger,
- Karl-Klaus Conzelmann,
- Jan Münch,
- Florian Ingo Schmidt,
- Daniel Sauter,
- Axel Imhof,
- Frank Kirchhoff,
- Konstantin Maria Johannes Sparrer
Affiliations
- Manuel Hayn
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
- Maximilian Hirschenberger
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
- Lennart Koepke
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
- Rayhane Nchioua
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
- Jan Hendrik Straub
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
- Susanne Klute
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
- Victoria Hunszinger
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
- Fabian Zech
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
- Caterina Prelli Bozzo
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
- Wasim Aftab
- Biomedical Center, Zentrallabor für Proteinanalytik (Protein Analysis Unit), Medical Faculty, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany; Graduate School for Quantitative Biosciences (QBM), Ludwig-Maximilians-University of Munich, 81377 Munich, Germany
- Maria Hønholt Christensen
- Institute of Innate Immunity, Medical Faculty, University of Bonn, 53127 Bonn, Germany
- Carina Conzelmann
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
- Janis Alexander Müller
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
- Smitha Srinivasachar Badarinarayan
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany; Institute of Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, 72076 Tübingen, Germany
- Christina Martina Stürzel
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
- Ignasi Forne
- Biomedical Center, Zentrallabor für Proteinanalytik (Protein Analysis Unit), Medical Faculty, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
- Steffen Stenger
- Institute for Medical Microbiology and Hygiene, Ulm University Medical Center, 89081 Ulm, Germany
- Karl-Klaus Conzelmann
- Max von Pettenkofer-Institute of Virology, Medical Faculty, and Gene Center, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
- Jan Münch
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
- Florian Ingo Schmidt
- Institute of Innate Immunity, Medical Faculty, University of Bonn, 53127 Bonn, Germany
- Daniel Sauter
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany; Institute of Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, 72076 Tübingen, Germany
- Axel Imhof
- Biomedical Center, Zentrallabor für Proteinanalytik (Protein Analysis Unit), Medical Faculty, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
- Frank Kirchhoff
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
- Konstantin Maria Johannes Sparrer
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany; Corresponding author
- Journal volume & issue
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Vol. 35,
no. 7
p. 109126
Abstract
Summary: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evades most innate immune responses but may still be vulnerable to some. Here, we systematically analyze the impact of SARS-CoV-2 proteins on interferon (IFN) responses and autophagy. We show that SARS-CoV-2 proteins synergize to counteract anti-viral immune responses. For example, Nsp14 targets the type I IFN receptor for lysosomal degradation, ORF3a prevents fusion of autophagosomes and lysosomes, and ORF7a interferes with autophagosome acidification. Most activities are evolutionarily conserved. However, SARS-CoV-2 Nsp15 antagonizes IFN signaling less efficiently than the orthologs of closely related RaTG13-CoV and SARS-CoV-1. Overall, SARS-CoV-2 proteins counteract autophagy and type I IFN more efficiently than type II or III IFN signaling, and infection experiments confirm potent inhibition by IFN-γ and -λ1. Our results define the repertoire and selected mechanisms of SARS-CoV-2 innate immune antagonists but also reveal vulnerability to type II and III IFN that may help to develop safe and effective anti-viral approaches.
