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Publications

Journal Article Epublish

PubMed: 40593736 DOI: 10.1038/s41467-025-60949-1

Human protein interaction networks of ancestral and variant SARS-CoV-2 in organ-specific cells and bodily fluids.

Nat Commun 16(1):5784

Authors: Kirsten Broderick, Mohamed Taha Moutaoufik, Tatiana Saccon, Ramy Malty, Shahreen Amin, Sadhna Phanse, Thomson Patrick Joseph, Mara Zilocchi, Ali Hosseinnia, Zoe Istace, Maryam Hajikarimlou, Sakib Abrar, Jade Fisher, Raelynn Brassard, Ranawaka Perera, Anil Kumar, Hiroyuki Aoki, Matineh Rahmatbakhsh, Matthew Jessulat, Darwyn Kobasa, Frank Dehne, Bhanu Prasad, Alla Gagarinova, M Joanne Lemieux, Alan Cochrane, Walid A Houry, Khaled A Aly, Ashkan Golshani, Mohan Babu

Affiliations

  • Department of Biochemistry, University of Regina, Regina, SK, Canada.
  • Faculty of Medical Sciences, University Mohammed VI Polytechnic, Benguerir, Morocco.
  • Department of Biology, Carleton University, Ontario, ON, Canada.
  • Department of Biochemistry, University of Alberta, Edmonton, AL, Canada.
  • Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada.
  • National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada.
  • Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada.
  • School of Computer Science, Carleton University, Ottawa, ON, Canada.
  • Department of Medicine, Regina Qu'Appelle Health Region, Regina, SK, Canada.
  • Department of Biology, University of New Brunswick, New Brunswick, N.B. Canada.
  • Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • Department of Biochemistry and Department of Chemistry, University of Toronto, Toronto, ON, Canada.
  • Department of Biochemistry, University of Regina, Regina, SK, Canada.

Abstract

Understanding SARS-CoV-2 human protein-protein interactions (PPIs) and the host response to infection is essential for developing effective COVID-19 antivirals. However, how the ancestral virus and its variants remodel virus-host protein assemblies in various organ-specific cells and bodily fluids remains unclear. Here, we conduct 639 affinity-purifications by tagging and expressing 28 SARS-CoV-2 and spike proteins from the ancestral virus and four variants in eight cell lines representing five mammalian organs and the immune system. Using mass spectrometry (MS), we identify both known and previously unreported SARS-CoV-2-human PPIs, highlighting similarities and differences across organ- or immune-derived cell lines and virus strains. Besides verifying the cell- and variant-specific PPIs, co-fractionation-MS analysis of COVID-19 patients' saliva confirm host PPI changes between SARS-CoV-2 strains. We discover that the NSP3 papain-like protease, a secreted protein, binds fibrinogen to induce abnormal blood clotting and interferon-induced proteins to evade host innate immune responses. Leveraging deep learning, we design peptide inhibitors that successfully blocked SARS-CoV-2 and variant replication in human liver cells, reversing virus-induced PPI alterations. Together, these findings provide molecular insights into SARS-CoV-2 biology, uncover reorganized viral-host protein assemblies during infection, and identify potential host therapeutic targets and inhibitors for developing antivirals against SARS-CoV-2 strains.

MeSH

Cells, Sars-Cov-2, Cell Line, Viruses, Severe Acute Respiratory Syndrome-Related Coronavirus, Antiviral Agents, Infections