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 H. Christensen, Carina Conzelmann, Janis A. Müller, Smitha Srinivasachar Badarinarayan, Christina M. Stürzel, Ignasi Forné, Steffen Stenger, Karl‐Klaus Conzelmann, Jan Münch, Florian I. Schmidt, Daniel Sauter, Axel Imhof, Frank Kirchhoff, Konstantin M. J. Sparrer
Abstract
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.