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

Manuel Hayn | Zendy; Maximilian Hirschenberger | Zendy; Lennart Koepke | Zendy; Rayhane Nchioua | Zendy; Jan Hendrik Straub | Zendy; Susanne Klute | Zendy; Victoria Hunszinger | Zendy; Fabian Zech | Zendy; Caterina Prelli Bozzo | Zendy; Wasim Aftab | Zendy; Maria H Christensen | Zendy; Carina Conzelmann | Zendy; Janis A. Müller | Zendy; Smitha Srinivasachar Badarinarayan | Zendy; Christina M. Stürzel | Zendy; Ignasi Forné | Zendy; Steffen Stenger | Zendy; KarlKlaus Conzelmann | Zendy; Jan Münch | Zendy; Florian I. Schmidt | Zendy; Daniel Sauter | Zendy; Axel Imhof | Zendy; Frank Kirchhoff | Zendy; Konstantin M. J. Sparrer | Zendy

Open Access

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

Author(s) -

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,

KarlKlaus Conzelmann,

Jan Münch,

Florian I. Schmidt,

Daniel Sauter,

Axel Imhof,

Frank Kirchhoff,

Konstantin M. J. Sparrer

Publication year - 2021

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2021.109126

Subject(s) - innate immune system , biology , interferon , immune system , autophagy , interferon type i , severe acute respiratory syndrome , immunology , receptor , virology , coronavirus , microbiology and biotechnology , covid-19 , genetics , disease , medicine , apoptosis , infectious disease (medical specialty) , pathology

SARS-CoV-2 evades most innate immune responses, but may still be vulnerable to some. Here, we systematically analyzed the impact of SARS-CoV-2 proteins on interferon (IFN) responses and autophagy. We show that SARS-CoV-2 proteins synergize to counteract antiviral 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 orthologues 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 confirmed 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.

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