Systematic analysis of innate immune antagonism reveals vulnerabilities of SARS-CoV-2

Hayn, M.; Hirschenberger, M.; Koepke, L.; Straub, J. H.; Nchioua, R.; Klute, S.; Prelli Bozzo, C.; Aftab, W.; Zech, F.; Conzelmann, C.; Mueller, J. A.; Srinivasachar Badarinarayan, S.; Stuerzel, C. M.; Forne, I.; Stenger, S.; Conzelmann, K.-K.; Muench, J.; Sauter, D.; Imhof, A.; Kirchhoff, F.; Sparrer, K. M. J.

doi:10.1101/2020.10.15.340612

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bioRxiv · 10.1101/2020.10.15.340612

Systematic analysis of innate immune antagonism reveals vulnerabilities of SARS-CoV-2

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Abstract

The innate immune system constitutes a powerful barrier against viral infections. However, it may fail because successful emerging pathogens, like SARS-CoV-2, evolved strategies to counteract it. Here, we systematically assessed the impact of 29 SARS-CoV-2 proteins on viral sensing, type I, II and III interferon (IFN) signaling, autophagy and inflammasome formation. Mechanistic analyses show that autophagy and type I IFN responses are effectively counteracted at different levels. For example, Nsp14 induces loss of the IFN receptor, whereas ORF3a disturbs autophagy at the Golgi/endosome interface. Comparative analyses revealed that antagonism of type I IFN and autophagy is largely conserved, except that SARS-CoV-1 Nsp15 is more potent in counteracting type I IFN than its SARS-CoV-2 ortholog. Altogether, however, SARS-CoV-2 counteracts type I IFN responses and autophagy much more efficiently than type II and III IFN signaling. Consequently, the virus is relatively resistant against exogenous IFN-/{beta} and autophagy modulation but remains highly vulnerable towards IFN-{gamma} and -{lambda} treatment. In combination, IFN-{gamma} and -{lambda} act synergistically, and drastically reduce SARS-CoV-2 replication at exceedingly low doses. Our results identify ineffective type I and II antagonism as weakness of SARS-CoV-2 that may allow to devise safe and effective anti-viral therapies based on targeted innate immune activation.

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Hayn, M., Hirschenberger, M., Koepke, L., Straub, J. H., Nchioua, R., Klute, S., Prelli Bozzo, C., Aftab, W., Zech, F., Conzelmann, C., Mueller, J. A., Srinivasachar Badarinarayan, S., Stuerzel, C. M., Forne, I., Stenger, S., Conzelmann, K.-K., Muench, J., Sauter, D., Imhof, A., Kirchhoff, F., Sparrer, K. M. J.. 2020-10-15. Systematic analysis of innate immune antagonism reveals vulnerabilities of SARS-CoV-2. https://doi.org/10.1101/2020.10.15.340612

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