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Systematic functional analysis of SARS-CoV-2 proteins uncovers viral innate immune antagonists and remaining vulnerabilities.

Cell reports

Authors: 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

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.

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

PMID: 33974846

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