Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms David Gordon, Joseph Hiatt, Mehdi Bouhaddou, Veronica Rezelj, Svenja Ulferts, Hannes Braberg, Alexander Jureka, Kirsten Obernier, Jeffrey Guo, Jyoti Batra, et al. To cite this version: David Gordon, Joseph Hiatt, Mehdi Bouhaddou, Veronica Rezelj, Svenja Ulferts, et al.. Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science, American Association for the Advancement of Science, 2020, 370 (6521), pp.eabe9403. 10.1126/science.abe9403. hal-03102291 HAL Id: hal-03102291 https://hal.archives-ouvertes.fr/hal-03102291 Submitted on 7 Jan 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Corrected 21 December 2020. See full text. RESEARCH ◥ RESULTS: Quantitative comparison of the 389 RESEARCH ARTICLE SUMMARY interactors of SARS-CoV-2, 366 of SARS-CoV-1, and 296 of MERS-CoV highlighted interactions CORONAVIRUS with host processes that are conserved across all three viruses, including where nonortholo- Comparative host-coronavirus protein interaction gous proteins from different virus strains seem to fill similar roles. We also localized each networks reveal pan-viral disease mechanisms individually-expressed viral protein by micros- copy and then raised and validated antisera David E. Gordon*,JosephHiatt*, Mehdi Bouhaddou*, Veronica V. Rezelj*,SvenjaUlferts*, Hannes Braberg*, against 14 SARS-CoV-2 proteins to determine Alexander S. Jureka*, Kirsten Obernier*,JeffreyZ.Guo*,JyotiBatra*, Robyn M. Kaake*,AndrewR.Weckstein*, their localization during infection. Tristan W. Owens*, Meghna Gupta*, Sergei Pourmal*, Erron W. Titus*, Merve Cakir* et al. On the basis of two independent genetic perturbation screens, we identified 73 host fac- tors that, when depleted, caused significant INTRODUCTION: The emergence of three lethal RATIONALE: Expanding on our recent SARS- changes in SARS-CoV-2 replication. From this coronaviruses in <20 years and the urgency of CoV-2 interactome, we mapped the virus-host list of potential drug targets, we validated the the COVID-19 pandemic have prompted ef- protein-protein interactions for SARS-CoV-1 biological and clinical relevance of Tom70, forts to develop new therapeutic strategies, in- and MERS-CoV and assessed the cellular lo- IL17RA, PGES-2, and SigmaR1. cluding by repurposing existing agents. After calization of each viral protein across the A3-Åcryo–electron microscopy structure of performing a comparative analysis of the three three strains. We conducted two genetic Tom70, a mitochondrial import receptor, in Downloaded from pathogenic human coronaviruses severe acute screens of SARS-CoV-2 interactors to priori- complex with SARS-CoV-2 ORF9b, provides in- respiratory syndrome coronavirus 1 (SARS- tize functionally-relevant host factors and sight into how ORF9b may modulate the host CoV-1), SARS-CoV-2, and Middle East respira- structurally characterized one virus-host in- immune response. Using curated genome-wide tory syndrome coronavirus (MERS-CoV), we teraction. We then tested the clinical rele- association study data, we found that individ- identified shared biology and host-directed vance of three more host factors by assessing uals with genotypes corresponding to higher drug targets to prioritize therapeutics with risk in genetic cohorts or observing effective- soluble IL17RA levels in plasma are at decreased potential for rapid deployment against cur- ness of host factor–targeting drugs in real- risk of COVID-19 hospitalization. http://science.sciencemag.org/ rent and future coronavirus outbreaks. world evidence. To demonstrate the value of our data for drug repurposing, we identified SARS-CoV-2 patients Protein-protein interactions Structure who were prescribed drugs against prioritized targets and asked how they fared compared with SARS-CoV-2 SARS-CoV-1 MERS-CoV carefully matched patients treated with clinically Tom70 similar drugs that do not inhibit SARS-CoV-2. Both indomethacin, an inhibitor of host factor PGES-2, and typical antipsychotics, selected for their interaction with sigma receptors, showed effectiveness against COVID-19 compared with on January 7, 2021 celecoxib and atypical antipsychotics, respectively. ORF9b Differential Interactions CONCLUSION: By employing an integrative and -1 0 +1 collaborative approach, we identified conserved Virus A Virus B Viral protein Protein complex mechanisms across three pathogenic corona- specific specific Shared Human protein Biological process virus strains and further investigated potential Localization of viral proteins drug targets. This versatile approach is broadly applicable to other infectious agents and dis- 14 novel Nsp9 ORF9b M ease areas. antibodies ▪ against SARS-CoV-2 The list of author affiliations is available in the full article online. proteins Cytoplasm Mitochondria ER/Golgi *These authors contributed equally to this work. Corresponding authors: Nevan J. Krogan (nevan.krogan@ Functional genetics Clinical ucsf.edu); Pedro Beltrao ([email protected]); Marco Vignuzzi ([email protected]); Christopher F. Basler Patients taking ([email protected]); Kliment A. Verba ([email protected]. Drug A Drug B edu); Oren S. Rosenberg ([email protected]); Andrew A. Peden ([email protected]); Robert Grosse Inpatient stay ([email protected]); Jeremy A. Rassen ([email protected]); Adolfo García-Sastre (adolfo. Hospital visit [email protected]) This is an open-access article distributed under the terms of SARS-CoV-2 protein SARS-CoV-1 protein MERS-CoV protein the Creative Commons Attribution license (https://creative- Host factor with decreased infectivity Host factor with increased infectivity Number of patients commons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided Overview of the approaches taken for systemic and functional comparison of pathogenic human the original work is properly cited. Cite this article as D. E. Gordon et al., Science 370, coronaviruses. (Left) Viral-human protein-protein interaction network mapping, viral protein localization studies, eabe9403 (2020). DOI: 10.1126/science.abe9403 and functional genetic screens provide key insights into the shared and individual characteristics of each virus. (Right) Structural studies and hypothesis testing in clinical datasets demonstrate the utility of this approach for READ THE FULL ARTICLE AT prioritizing therapeutic strategies. Nsp, nonstructural protein; ORF, open reading frame; ER, endoplasmic reticulum. https://doi.org/10.1126/science.abe9403 Gordon et al., Science 370, 1181 (2020) 4 December 2020 1of1 Corrected 21 December 2020. See full text. RESEARCH ◥ RESEARCH ARTICLE 1Quantitative Biosciences Institute (QBI) COVID-19 Research Group (QCRG), San Francisco, CA 94158, USA. 2QBI, University of California, San Francisco, CA 94158, USA. 3Department of CORONAVIRUS Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA. 4J. David Gladstone Institutes, San Francisco, CA 94158, USA. 5Medical Scientist Training Comparative host-coronavirus protein interaction Program, University of California, San Francisco, CA 94143, USA. 6Department of Microbiology and Immunology, University networks reveal pan-viral disease mechanisms of California, San Francisco, CA 94143, USA. 7Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA. 8Viral Populations and Pathogenesis 1,2,3,4 1,4,5,6,7 1,2,3,4 8 Unit, CNRS UMR 3569, Institut Pasteur, 75724, Paris, cedex 15, David E. Gordon *, Joseph Hiatt *, Mehdi Bouhaddou *, Veronica V. Rezelj *, France. 9Institute for Clinical and Experimental Pharmacology Svenja Ulferts9*, Hannes Braberg1,2,3,4*, Alexander S. Jureka10*, Kirsten Obernier1,2,3,4*, and Toxicology I, University of Freiburg, 79104 Freiburg, 10 Jeffrey Z. Guo1,2,3,4*, Jyoti Batra1,2,3,4*, Robyn M. Kaake1,2,3,4*, Andrew R. Weckstein11*, Germany. Center for Microbial Pathogenesis, Institute for 12* 12* 12* 12* 1,2,3,4* Biomedical Sciences, Georgia State University, Atlanta, GA Tristan W. Owens , Meghna Gupta , Sergei Pourmal , Erron W. Titus , Merve Cakir , 30303, USA. 11Aetion, Inc., New York, NY 10001, USA. 12QBI Margaret Soucheray1,2,3,4, Michael McGregor1,2,3,4, Zeynep Cakir1,2,3,4, Gwendolyn Jang1,2,3,4, Coronavirus Research Group Structural Biology Consortium, ’ 13 1,2,14 1,2,3,15 1,2,3,4 1,2,3,4 University of California, San Francisco, CA 94158, USA. Matthew J. O Meara , Tia A. Tummino , Ziyang Zhang , Helene Foussard , Ajda Rojc , 13 1,2,3,4 1,2,3,4 1,2,3,4 1,2,3,4 1,2,3,4 Department of Computational Medicine and Bioinformatics, Yuan Zhou , Dmitry Kuchenov , Ruth Hüttenhain , Jiewei Xu , Manon Eckhardt , University of Michigan, Ann Arbor, MI 48109, USA. 14Department 1,2,3,4 1,2 1,2,3,4 1,2,3,4 Danielle L. Swaney , Jacqueline M. Fabius , Manisha Ummadi , Beril Tutuncuoglu , of Pharmaceutical Chemistry, University of California, San Ujjwal Rathore1,2,3,4, Maya Modak1,2,3,4, Paige Haas1,2,3,4,