RT Journal Article
SR Electronic
T1 Systematic analysis of innate immune antagonism reveals vulnerabilities of SARS-CoV-2
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.10.15.340612
DO 10.1101/2020.10.15.340612
A1 Manuel Hayn
A1 Maximilian Hirschenberger
A1 Lennart Koepke
A1 Jan H Straub
A1 Rayhane Nchioua
A1 Susanne Klute
A1 Caterina Prelli Bozzo
A1 Wasim Aftab
A1 Fabian Zech
A1 Carina Conzelmann
A1 Janis A Müller
A1 Smitha Srinivasachar Badarinarayan
A1 Christina M Stürzel
A1 Ignasi Forne
A1 Steffen Stenger
A1 Karl-Klaus Conzelmann
A1 Jan Münch
A1 Daniel Sauter
A1 Axel Imhof
A1 Frank Kirchhoff
A1 Konstantin MJ Sparrer
YR 2020
UL http://biorxiv.org/content/early/2020/10/15/2020.10.15.340612.abstract
AB The innate immune system efficiently defends the human host against viral pathogens. Thus, viruses evolved strategies to counteract immune activation. Here, we systematically analysed the impact of 29 SARS-CoV-2 encoded proteins on three major arms of our cell-intrinsic innate immune defences: interferon (IFN) induction, cytokine signalling and autophagy. Subsequent mechanistic analyses revealed that SARS-CoV-2 proteins target the respective signalling cascades at multiple steps. For example, we show that Nsp14 reduces endogenous IFN receptor levels and ORF3a and ORF7a perturb the late endosomal/trans-Golgi network. Our data demonstrates that most antagonistic activities are conserved between proteins encoded by SARS-CoV-2, the closely related bat RaTG13-CoV and the highly pathogenic SARS-CoV-1. However, SARS-CoV-1 Nsp15 is strikingly more potent in suppressing IFN induction and signalling than its SARS-CoV-2 counterpart. This may help explain the lower pathogenicity of SARS-CoV-2, which facilitated its rapid spread. Overall our analyses revealed that IFN-γ and IFN-λ1 signalling are antagonised the least, leaving SARS-CoV-2 highly susceptible to these two cytokines. Their combination synergistically potentiated the anti-viral effects against SARS-CoV-2 at low concentrations. Taken together, our results allow an explanation for differences in susceptibility towards IFNs and provide evidence that rational immune activation may be an effective future therapeutic strategy against SARS-CoV-2.Competing Interest StatementThe authors have declared no competing interest.