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

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

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...

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Main 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
Format: Article
Language:English
Published: Nature Portfolio 2025-07-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-60949-1
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Summary: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.
ISSN:2041-1723

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