Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms

Gordon, D. E. et al. (2020) Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science, 370(6521), eabe9403. (doi: 10.1126/science.abe9403) (PMID:33060197) (PMCID:PMC7808408)

Abstract

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a grave threat to public health and the global economy. SARS-CoV-2 is closely related to the more lethal but less transmissible coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). Here, we have carried out comparative viral-human protein-protein interaction and viral protein localization analyses for all three viruses. Subsequent functional genetic screening identified host factors that functionally impinge on coronavirus proliferation, including Tom70, a mitochondrial chaperone protein that interacts with both SARS-CoV-1 and SARS-CoV-2 ORF9b, an interaction we structurally characterized using cryo–electron microscopy. Combining genetically validated host factors with both COVID-19 patient genetic data and medical billing records identified molecular mechanisms and potential drug treatments that merit further molecular and clinical study.

• Item Type: Articles
• Additional Information: Funding: This research was funded by grants from the National Institutes of Health (NIH) (P01AI063302, P50AI150476, R01AI120694, R01AI122747, R01AI143292, U19AI135972, and U19AI135990 to N.J.K.; P01AI120943 and R01AI143292 to C.F.B.; and U19 AI135990 to T.I.); by the National Institute of Allergy and Infectious Diseases (NIAID) R01AI128214 to O.S.R.; by the National Institute of Neurological Disorders and Stroke R01 NS089713, the NIH Office of the Director AI150476, and NIGMS R01 GM24485 to R.M.S.; by a Fast Grant for COVID-19 from the Emergent Ventures program at the Mercatus Center of George Mason University (N.J.K.) and a separate Fast Grant for COVID-19 (C.F.B.); by the Roddenberry Foundation Gladstone Institutes to K.S.P. and N.J.K.; from the Defense Advanced Research Projects Agency (HR0011-19-2-0020 to B.S., N.J.K., K.A.V., D.A.A., A.G.-S., and K.M.S.; HR0011-20-2-0040 to M.B.F.); NIGMS R35GM122481 (to B.S.); by CRIP (Center for Research for Influenza Pathogenesis), a NIAID supported Center of Excellence for Influenza Research and Surveillance (CEIRS, contract no. HHSN272201400008C) to A.G.-S.; by supplements to NIAID grant U19AI135972 and DoD grant W81XWH-20-1-0270 to A.G.-S.; by the Bill and Melinda Gates Foundation (INV-006099) and BARDA (ASPR-20-01495) to M.B.F.; by Howard Hughes Medical Institute to K.S.; by Damon Runyon Cancer Research Foundation DRG-2402-20 to C.P.; by Burroughs Wellcome Fund 1019894 to N.He.; by the Chan Zuckerberg Initiative to O.S.R. and T.Ko.; by Cytoscape: A modeling platform for biomolecular networks (NHGRI R01 HG009979) to T.I.; by the generous support of the JPB Foundation, the Open Philanthropy Project [research grant 2020-215611 (5384)] and by anonymous donors to A.G.-S.; a Laboratoire d’Excellence grant ANR-10-LABX-62-IBEID and the URGENCE COVID-19 Institut Pasteur fundraising campaign to M.V and N.Jo.; by grants from the BBSRC (BB/S009566/1 and BB/L002841/1) to A.A.P. and D.W. and by BBSRC White Rose DTP (BB/J014443/1) to A.S.S.-S.; by The Augusta University–Georgia State University Seed Grant program to C.F.B.; by the MRC grant MC PC 19026 to M.P.; by the MRC Grant MC_UU_12016/2 to D.A.; by the Medical Research Council (MC_UU_12016/2) to D.R.A.; by the DFG under Germany’s Excellence Strategy (EXC-2189, project ID 390939984 to R.G.); and funding from F. Hoffmann-La Roche and Vir Biotechnology and gifts from The Ron Conway Family and Vir Biotechnology to the Quantitative Biosciences Institute Coronavirus Research Group (QCRG). This work was supported by the Excellence in Research Award (ERA) from the Laboratory for Genomics Research, a collaboration between the Innovative Genomics Institute of UC Berkeley/UCSF and GlaxoSmithKline (133122P to M.O. and N.J.K.). J.H. was supported by the UCSF Medical Scientist Training Program (T32GM007618); P.F. was supported by the UCSF Medical Scientist Training Program (T32GM007618) and the NIH-NIAID (F30AI143401); M.B. was supported by the NCI at the NIH (F32CA239333); H.T.K. was supported by the NIH (K99GM138753); K.H. was supported by the National Science Foundation (1650113); B.T. was supported by the NIH (F32 CA239336); U.S.C. was supported by the National Institute of General Medical Sciences (F32GM137463). The QCRG Structural Biology Consortium has received support from: Quantitative Biosciences Institute, Defense Advance Research Projects Agency [HR0011-19-2-0020 to D.A.A. and K.A.V.; B.S., primary investigator (PI)], FastGrants COVID-19 grant (K.A.V., PI), Laboratory For Genomics Research (O.S.R., PI), and Laboratory For Genomics Research (R.M.S., PI).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Palmarini, Professor Massimo and Rihn, Dr Suzannah and Patel, Professor Arvind
• Authors: Gordon, D. E., Hiatt, J., Bouhaddou, M., Rezelj, V. V., Ulferts, S., Braberg, H., Jureka, A. S., Obernier, K., Guo, J. Z., Batra, J., Kaake, R. M., Weckstein, A. R., Owens, T. W., Gupta, M., Pourmal, S., Titus, E. W., Cakir, M., Soucheray, M., McGregor, M., Cakir, Z., Jang, G., O’Meara, M. J., Tummino, T. A., Zhang, Z., Foussard, H., Rojc, A., Zhou, Y., Kuchenov, D., Hüttenhain, R., Xu, J., Eckhardt, M., Swaney, D. L., Fabius, J. M., Ummadi, M., Tutuncuoglu, B., Rathore, U., Modak, M., Haas, P., Haas, K. M., Naing, Z. Z. C., Pulido, E. H., Shi, Y., Barrio-Hernandez, I., Memon, D., Petsalaki, E., Dunham, A., Marrero, M. C., Burke, D., Koh, C., Vallet, T., Silvas, J. A., Azumaya, C. M., Billesbølle, C., Brilot, A. F., Campbell, M. G., Diallo, A., Dickinson, M. S., Diwanji, D., Herrera, N., Hoppe, N., Kratochvil, H. T., Liu, Y., Merz, G. E., Moritz, M., Nguyen, H. C., Nowotny, C., Puchades, C., Rizo, A. N., Schulze-Gahmen, U., Smith, A. M., Sun, M., Young, I. D., Zhao, J., Asarnow, D., Biel, J., Bowen, A., Braxton, J. R., Chen, J., Chio, C. M., Chio, U. S., Deshpande, I., Doan, L., Faust, B., Flores, S., Jin, M., Kim, K., Lam, V. L., Li, F., Li, J., Li, Y.-L., Li, Y., Liu, X., Lo, M., Lopez, K. E., Melo, A. A., Moss, F. R., Nguyen, P., Paulino, J., Pawar, K. I., Peters, J. K., Pospiech, T. H., Safari, M., Sangwan, S., Schaefer, K., Thomas, P. V., Thwin, A. C., Trenker, R., Tse, E., Tsui, T. K. M., Wang, F., Whitis, N., Yu, Z., Zhang, K., Zhang, Y., Zhou, F., Saltzberg, D., Hodder, A. J., Shun-Shion, A. S., Williams, D. M., White, K. M., Rosales, R., Kehrer, T., Miorin, L., Moreno, E., Patel, A. H., Rihn, S., Khalid, M. M., Vallejo-Gracia, A., Fozouni, P., Simoneau, C. R., Roth, T. L., Wu, D., Karim, M. A., Ghoussaini, M., Dunham, I., Berardi, F., Weigang, S., Chazal, M., Park, J., Logue, J., McGrath, M., Weston, S., Haupt, R., Hastie, C. J., Elliott, M., Brown, F., Burness, K. A., Reid, E., Dorward, M., Johnson, C., Wilkinson, S. G., Geyer, A., Giesel, D. M., Baillie, C., Raggett, S., Leech, H., Toth, R., Goodman, N., Keough, K. C., Lind, A. L., Klesh, R. J., Hemphill, K. R., Carlson-Stevermer, J., Oki, J., Holden, K., Maures, T., Pollard, K. S., Sali, A., Agard, D. A., Cheng, Y., Fraser, J. S., Frost, A., Jura, N., Kortemme, T., Manglik, A., Southworth, D. R., Stroud, R. M., Alessi, D. R., Davies, P., Frieman, M. B., Ideker, T., Abate, C., Jouvenet, N., Kochs, G., Shoichet, B., Ott, M., Palmarini, M., Shokat, K. M., García-Sastre, A., Rassen, J. A., Grosse, R., Rosenberg, O. S., Verba, K. A., Basler, C. F., Vignuzzi, M., Peden, A. A., Beltrao, P., Krogan, N. J., Owens, T. W., Gupta, M., Pourmal, S., Titus, E. W., Azumaya, C. M., Billesbølle, C., Brilot, A. F., Campbell, M. G., Diallo, A., Dickinson, M. S., Diwanji, D., Herrera, N., Hoppe, N., Kratochvil, H. T., Liu, Y., Merz, G. E., Moritz, M., Nguyen, H. C., Nowotny, C., Puchades, C., Rizo, A. N., Schulze-Gahmen, U., Smith, A. M., Sun, M., Young, I. D., Zhao, J., Asarnow, D., Biel, J., Bowen, A., Braxton, J. R., Chen, J., Chio, C. M., Chio, U. S., Deshpande, I., Doan, L., Faust, B., Flores, S., Jin, M., Kim, K., Lam, V. L., Li, F., Li, J., Li, Y.-L., Li, Y., Liu, X., Lo, M., Lopez, K. E., Melo, A. A., Moss, F. R., Nguyen, P., Paulino, J., Pawar, K. I., Peters, J. K., Pospiech, T. H., Safari, M., Sangwan, S., Schaefer, K., Thomas, P. V., Thwin, A. C., Trenker, R., Tse, E., Tsui, T. K. M., Wang, F., Whitis, N., Yu, Z., Zhang, K., Zhang, Y., Zhou, F., Trinidad, D., Agard, D. A., Cheng, Y., Fraser, J. S., Frost, A., Jura, N., Kortemme, T., Manglik, A., Southworth, D. R., Stroud, R. M., Rosenberg, O. S., Verba, K. A., Damas, J., Hughes, G. M., Keough, K. C., Painter, C. A., Persky, N. S., Corbo, M., Kirilenko, B., Hiller, M., Koepfli, K.-P., Kaplow, I., Wirthlin, M., Pfenning, A. R., Zhao, H., Genereux, D. P., Swofford, R., Lind, A., Pollard, K. S., Ryderq, O. A., Nweeia, M. T., Meadows, J., Dong, M., Wallerman, O., Marinescu, V., Lindblad-Toh, K., Ray, D. A., Power, S., Teeling, E. C., Chauhan, G., Li, S. X., Karlsson, E. K., and Lewin, H. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Science
• Publisher: American Association for the Advancement of Science (AAAS)
• ISSN: 0036-8075
• ISSN (Online): 1095-9203
• Published Online: 15 October 2020
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Science 370(6521): eabe9403
• Publisher Policy: Reproduced under a Creative Commons licence