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 and Mohan Babu ()
Additional contact information
Kirsten Broderick: University of Regina
Mohamed Taha Moutaoufik: University of Regina
Tatiana Saccon: University of Regina
Ramy Malty: University of Regina
Shahreen Amin: University of Regina
Sadhna Phanse: University of Regina
Thomson Patrick Joseph: University of Regina
Mara Zilocchi: University of Regina
Ali Hosseinnia: University of Regina
Zoe Istace: University of Regina
Maryam Hajikarimlou: Carleton University
Sakib Abrar: University of Regina
Jade Fisher: University of Regina
Raelynn Brassard: University of Alberta
Ranawaka Perera: University of Pennsylvania
Anil Kumar: University of Saskatchewan
Hiroyuki Aoki: University of Regina
Matineh Rahmatbakhsh: University of Regina
Matthew Jessulat: University of Regina
Darwyn Kobasa: Public Health Agency of Canada
Frank Dehne: Carleton University
Bhanu Prasad: Regina Qu’Appelle Health Region
Alla Gagarinova: University of Regina
M. Joanne Lemieux: University of Alberta
Alan Cochrane: University of Toronto
Walid A. Houry: University of Toronto
Khaled A. Aly: University of Regina
Ashkan Golshani: Carleton University
Mohan Babu: University of Regina

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-60949-1 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60949-1

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-60949-1

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().