Human protein interaction networks of ancestral and variant SARS-CoV-2 in organ-specific cells and bodily fluids
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
Nature Communications, 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 A list of authors and their affiliations appears at the end of the paper 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. The ancestral SARS-CoV-2 virus and its variants of concern (e.g., Alpha B. 1.1.7, Beta B.1.351, Gamma P.1, Delta B.1.617.2, Omicron B.1.1.529) or interest (e.g., Lambda C.37) causing coronavirus disease 2019 (COVID-19) have been detected in various organs (e.g., liver, lung, kidney) and bodily fluids (e.g., saliva) 1,2 , with organ-specific SARS-CoV-2 evolution observed in long COVID cases 3 . Studies using mass spectrometry (MS)-based proteomics and yeast-two hybrid (Y2H) assays highlight the roles for SARS-CoV-2 proteins in pathogenesis and host factors or processes targeted during infection [4] [5] [6] [7] [8] . Recent findings reveal that virus-host protein-protein interactions (PPIs) differ in variants, aiding immune evasion 9 . However, published studies focused on cell-based models or peripheral blood mononuclear cells, leaving gaps in understanding how SARS-CoV-2 and its variants remodel host responses and PPIs in various organs and fluids, particularly in saliva, a key site for SARS-CoV-2 infection and transmission 2 . While repurposed drugs and vaccines have reduced COVID-19 deaths, the need for improved therapeutics or organ-specific treatments continues. Targeting virus-host interface is a key strategy for antiviral development, with..
Reporting summary Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.
Author contributions
Competing interests The authors declare no competing interests.
Additional information Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s41467-025-60949-1 . Correspondence and requests for materials should be addressed to Mohan Babu. Peer review information Nature Communications thanks the anonymous reviewers for their contribution to the peer review of this work. A peer review file is available. Reprints and permissions information is available at http://www.nature.com/reprints Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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