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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-07-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60949-1 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849402152932343808 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Kirsten Broderick |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-7162871cc4a348f0800607faf751d6c8 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-7162871cc4a348f0800607faf751d6c82025-08-20T03:37:37ZengNature PortfolioNature Communications2041-17232025-07-0116112010.1038/s41467-025-60949-1Human protein interaction networks of ancestral and variant SARS-CoV-2 in organ-specific cells and bodily fluidsKirsten Broderick0Mohamed Taha Moutaoufik1Tatiana Saccon2Ramy Malty3Shahreen Amin4Sadhna Phanse5Thomson Patrick Joseph6Mara Zilocchi7Ali Hosseinnia8Zoe Istace9Maryam Hajikarimlou10Sakib Abrar11Jade Fisher12Raelynn Brassard13Ranawaka Perera14Anil Kumar15Hiroyuki Aoki16Matineh Rahmatbakhsh17Matthew Jessulat18Darwyn Kobasa19Frank Dehne20Bhanu Prasad21Alla Gagarinova22M. Joanne Lemieux23Alan Cochrane24Walid A. Houry25Khaled A. Aly26Ashkan Golshani27Mohan Babu28Department of Biochemistry, University of ReginaDepartment of Biochemistry, University of ReginaDepartment of Biochemistry, University of ReginaDepartment of Biochemistry, University of ReginaDepartment of Biochemistry, University of ReginaDepartment of Biochemistry, University of ReginaDepartment of Biochemistry, University of ReginaDepartment of Biochemistry, University of ReginaDepartment of Biochemistry, University of ReginaDepartment of Biochemistry, University of ReginaDepartment of Biology, Carleton UniversityDepartment of Biochemistry, University of ReginaDepartment of Biochemistry, University of ReginaDepartment of Biochemistry, University of AlbertaDepartment of Microbiology, Perelman School of Medicine, University of PennsylvaniaDepartment of Biochemistry, Microbiology and Immunology, University of SaskatchewanDepartment of Biochemistry, University of ReginaDepartment of Biochemistry, University of ReginaDepartment of Biochemistry, University of ReginaNational Microbiology Laboratory, Public Health Agency of CanadaSchool of Computer Science, Carleton UniversityDepartment of Medicine, Regina Qu’Appelle Health RegionDepartment of Biochemistry, University of ReginaDepartment of Biochemistry, University of AlbertaDepartment of Molecular Genetics, University of TorontoDepartment of Biochemistry and Department of Chemistry, University of TorontoDepartment of Biochemistry, University of ReginaDepartment of Biology, Carleton UniversityDepartment of Biochemistry, University of ReginaAbstract 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.https://doi.org/10.1038/s41467-025-60949-1 |
| spellingShingle | 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 Human protein interaction networks of ancestral and variant SARS-CoV-2 in organ-specific cells and bodily fluids Nature Communications |
| title | Human protein interaction networks of ancestral and variant SARS-CoV-2 in organ-specific cells and bodily fluids |
| title_full | Human protein interaction networks of ancestral and variant SARS-CoV-2 in organ-specific cells and bodily fluids |
| title_fullStr | Human protein interaction networks of ancestral and variant SARS-CoV-2 in organ-specific cells and bodily fluids |
| title_full_unstemmed | Human protein interaction networks of ancestral and variant SARS-CoV-2 in organ-specific cells and bodily fluids |
| title_short | Human protein interaction networks of ancestral and variant SARS-CoV-2 in organ-specific cells and bodily fluids |
| title_sort | human protein interaction networks of ancestral and variant sars cov 2 in organ specific cells and bodily fluids |
| url | https://doi.org/10.1038/s41467-025-60949-1 |
| work_keys_str_mv | AT kirstenbroderick humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT mohamedtahamoutaoufik humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT tatianasaccon humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT ramymalty humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT shahreenamin humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT sadhnaphanse humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT thomsonpatrickjoseph humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT marazilocchi humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT alihosseinnia humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT zoeistace humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT maryamhajikarimlou humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT sakibabrar humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT jadefisher humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT raelynnbrassard humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT ranawakaperera humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT anilkumar humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT hiroyukiaoki humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT matinehrahmatbakhsh humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT matthewjessulat humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT darwynkobasa humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT frankdehne humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT bhanuprasad humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT allagagarinova humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT mjoannelemieux humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT alancochrane humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT walidahoury humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT khaledaaly humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT ashkangolshani humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids AT mohanbabu humanproteininteractionnetworksofancestralandvariantsarscov2inorganspecificcellsandbodilyfluids |