Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV.

Stukalov, Alexey; Girault, Virginie; Grass, Vincent; Karayel, Ozge; Bergant, Valter; Urban, Christian; Haas, Darya A; Huang, Yiqi; Oubraham, Lila; Wang, Anqi; Hamad, M Sabri; Piras, Antonio; Hansen, Fynn M; Tanzer, Maria C; Paron, Igor; Zinzula, Luca; Engleitner, Thomas; Reinecke, Maria; Lavacca, Teresa M; Ehmann, Rosina; ... (2021). Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature, 594(7862), pp. 246-252. Springer Nature 10.1038/s41586-021-03493-4

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The emergence and global spread of SARS-CoV-2 has resulted in the urgent need for an in-depth understanding of molecular functions of viral proteins and their interactions with the host proteome. Several individual omics studies have extended our knowledge of COVID-19 pathophysiology1-10. Integration of such datasets to obtain a holistic view of virus-host interactions and to define the pathogenic properties of SARS-CoV-2 is limited by the heterogeneity of the experimental systems. Here we report a concurrent multi-omics study of SARS-CoV-2 and SARS-CoV. Using state-of-the-art proteomics, we profiled the interactomes of both viruses, as well as their influence on the transcriptome, proteome, ubiquitinome and phosphoproteome of a lung-derived human cell line. Projecting these data onto the global network of cellular interactions revealed crosstalk between the perturbations taking place upon infection with SARS-CoV-2 and SARS-CoV at different levels and enabled identification of distinct and common molecular mechanisms of these closely related coronaviruses. The TGF-β pathway, known for its involvement in tissue fibrosis, was specifically dysregulated by SARS-CoV-2 ORF8 and autophagy was specifically dysregulated by SARS-CoV-2 ORF3. The extensive dataset (available at https://covinet.innatelab.org ) highlights many hotspots that could be targeted by existing drugs and may be used to guide rational design of virus- and host-directed therapies, which we exemplify by identifying inhibitors of kinases and matrix metalloproteases with potent antiviral effects against SARS-CoV-2.

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