tetano
Editor, Senior Moderator
Cell Rep
. 2021 Apr 27;109126.
doi: 10.1016/j.celrep.2021.109126. Online ahead of print.
Systematic functional analysis of SARS-CoV-2 proteins uncovers viral innate immune antagonists and remaining vulnerabilities
Manuel Hayn[SUP] 1 [/SUP], Maximilian Hirschenberger[SUP] 1 [/SUP], Lennart Koepke[SUP] 1 [/SUP], Rayhane Nchioua[SUP] 1 [/SUP], Jan Hendrik Straub[SUP] 1 [/SUP], Susanne Klute[SUP] 1 [/SUP], Victoria Hunszinger[SUP] 1 [/SUP], Fabian Zech[SUP] 1 [/SUP], Caterina Prelli Bozzo[SUP] 1 [/SUP], Wasim Aftab[SUP] 2 [/SUP], Maria H?nholt Christensen[SUP] 3 [/SUP], Carina Conzelmann[SUP] 1 [/SUP], Janis Alexander M?ller[SUP] 1 [/SUP], Smitha Srinivasachar Badarinarayan[SUP] 4 [/SUP], Christina Martina St?rzel[SUP] 1 [/SUP], Ignasi Forne[SUP] 5 [/SUP], Steffen Stenger[SUP] 6 [/SUP], Karl-Klaus Conzelmann[SUP] 7 [/SUP], Jan M?nch[SUP] 1 [/SUP], Florian Ingo Schmidt[SUP] 3 [/SUP], Daniel Sauter[SUP] 4 [/SUP], Axel Imhof[SUP] 5 [/SUP], Frank Kirchhoff[SUP] 1 [/SUP], Konstantin Maria Johannes Sparrer[SUP] 8 [/SUP]
Affiliations
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-? and -?1. 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.
Keywords: COVID-19; SARS-CoV; SARS-CoV-2; autophagy; cytokine; immune evasion; innate immunity; interferon.
. 2021 Apr 27;109126.
doi: 10.1016/j.celrep.2021.109126. Online ahead of print.
Systematic functional analysis of SARS-CoV-2 proteins uncovers viral innate immune antagonists and remaining vulnerabilities
Manuel Hayn[SUP] 1 [/SUP], Maximilian Hirschenberger[SUP] 1 [/SUP], Lennart Koepke[SUP] 1 [/SUP], Rayhane Nchioua[SUP] 1 [/SUP], Jan Hendrik Straub[SUP] 1 [/SUP], Susanne Klute[SUP] 1 [/SUP], Victoria Hunszinger[SUP] 1 [/SUP], Fabian Zech[SUP] 1 [/SUP], Caterina Prelli Bozzo[SUP] 1 [/SUP], Wasim Aftab[SUP] 2 [/SUP], Maria H?nholt Christensen[SUP] 3 [/SUP], Carina Conzelmann[SUP] 1 [/SUP], Janis Alexander M?ller[SUP] 1 [/SUP], Smitha Srinivasachar Badarinarayan[SUP] 4 [/SUP], Christina Martina St?rzel[SUP] 1 [/SUP], Ignasi Forne[SUP] 5 [/SUP], Steffen Stenger[SUP] 6 [/SUP], Karl-Klaus Conzelmann[SUP] 7 [/SUP], Jan M?nch[SUP] 1 [/SUP], Florian Ingo Schmidt[SUP] 3 [/SUP], Daniel Sauter[SUP] 4 [/SUP], Axel Imhof[SUP] 5 [/SUP], Frank Kirchhoff[SUP] 1 [/SUP], Konstantin Maria Johannes Sparrer[SUP] 8 [/SUP]
Affiliations
- PMID: 33974846
- PMCID: PMC8078906
- DOI: 10.1016/j.celrep.2021.109126
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-? and -?1. 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.
Keywords: COVID-19; SARS-CoV; SARS-CoV-2; autophagy; cytokine; immune evasion; innate immunity; interferon.