Viral anti‐inflammatory serpin reduces immuno‐coagulopathic pathology in SARS‐CoV‐2 mouse models of infection
Abstract SARS‐CoV‐2 acute respiratory distress syndrome (ARDS) induces uncontrolled lung inflammation and coagulopathy with high mortality. Anti‐viral drugs and monoclonal antibodies reduce early COVID‐19 severity, but treatments for late‐stage immuno‐thrombotic syndromes and long COVID are limited....
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2023-09-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202317376 |
| _version_ | 1797280424138899456 |
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| author | Liqiang Zhang Yize (Henry) Li Karen Kibler Simona Kraberger Arvind Varsani Julie Turk Nora Elmadbouly Emily Aliskevich Laurel Spaccarelli Bereket Estifanos Junior Enow Isabela Rivabem Zanetti Nicholas Saldevar Efrem Lim Jessika Schlievert Kyle Browder Anjali Wilson Fernando Arcos Juan Aubrey Pinteric Aman Garg Henna Monder Rohan Saju Savanah Gisriel Bertram Jacobs Timothy L Karr Esther Borges Florsheim Vivek Kumar John Wallen Masmudur Rahman Grant McFadden Brenda G Hogue Alexandra R Lucas |
| author_facet | Liqiang Zhang Yize (Henry) Li Karen Kibler Simona Kraberger Arvind Varsani Julie Turk Nora Elmadbouly Emily Aliskevich Laurel Spaccarelli Bereket Estifanos Junior Enow Isabela Rivabem Zanetti Nicholas Saldevar Efrem Lim Jessika Schlievert Kyle Browder Anjali Wilson Fernando Arcos Juan Aubrey Pinteric Aman Garg Henna Monder Rohan Saju Savanah Gisriel Bertram Jacobs Timothy L Karr Esther Borges Florsheim Vivek Kumar John Wallen Masmudur Rahman Grant McFadden Brenda G Hogue Alexandra R Lucas |
| author_sort | Liqiang Zhang |
| collection | DOAJ |
| description | Abstract SARS‐CoV‐2 acute respiratory distress syndrome (ARDS) induces uncontrolled lung inflammation and coagulopathy with high mortality. Anti‐viral drugs and monoclonal antibodies reduce early COVID‐19 severity, but treatments for late‐stage immuno‐thrombotic syndromes and long COVID are limited. Serine protease inhibitors (SERPINS) regulate activated proteases. The myxoma virus‐derived Serp‐1 protein is a secreted immunomodulatory serpin that targets activated thrombotic, thrombolytic, and complement proteases as a self‐defense strategy to combat clearance. Serp‐1 is effective in multiple animal models of inflammatory lung disease and vasculitis. Here, we describe systemic treatment with purified PEGylated Serp‐1 as a therapy for immuno‐coagulopathic complications during ARDS. Treatment with PEGSerp‐1 in two mouse‐adapted SARS‐CoV‐2 models in C57Bl/6 and BALB/c mice reduced lung and heart inflammation, with improved outcomes. PEGSerp‐1 significantly reduced M1 macrophages in the lung and heart by modifying urokinase‐type plasminogen activator receptor (uPAR), thrombotic proteases, and complement membrane attack complex (MAC). Sequential changes in gene expression for uPAR and serpins (complement and plasminogen inhibitors) were observed. PEGSerp‐1 is a highly effective immune‐modulator with therapeutic potential for severe viral ARDS, immuno‐coagulopathic responses, and Long COVID. |
| first_indexed | 2024-03-07T16:40:04Z |
| format | Article |
| id | doaj.art-173774a4d3874632894de3a50c2ec7e5 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T16:40:04Z |
| publishDate | 2023-09-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-173774a4d3874632894de3a50c2ec7e52024-03-03T08:22:05ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-09-01159n/an/a10.15252/emmm.202317376Viral anti‐inflammatory serpin reduces immuno‐coagulopathic pathology in SARS‐CoV‐2 mouse models of infectionLiqiang Zhang0Yize (Henry) Li1Karen Kibler2Simona Kraberger3Arvind Varsani4Julie Turk5Nora Elmadbouly6Emily Aliskevich7Laurel Spaccarelli8Bereket Estifanos9Junior Enow10Isabela Rivabem Zanetti11Nicholas Saldevar12Efrem Lim13Jessika Schlievert14Kyle Browder15Anjali Wilson16Fernando Arcos Juan17Aubrey Pinteric18Aman Garg19Henna Monder20Rohan Saju21Savanah Gisriel22Bertram Jacobs23Timothy L Karr24Esther Borges Florsheim25Vivek Kumar26John Wallen27Masmudur Rahman28Grant McFadden29Brenda G Hogue30Alexandra R Lucas31Center for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USACenter of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USACenter of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USACenter of Fundamental and Applied Microbiomics Biodesign Institute, Arizona State University Tempe AZ USASchool of Life Sciences Arizona State University Tempe AZ USACenter for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USACenter for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USACenter for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USACenter for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USACenter of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USACenter of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USACenter for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USACenter for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USASchool of Life Sciences Arizona State University Tempe AZ USACenter of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USACenter for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USACenter of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USACenter of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USACenter for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USACenter for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USACenter for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USACenter for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USACenter for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USACenter of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USACenter for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USACenter of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USANew Jersey Institute of Technology Newark NJ USAColt Advisors LLC Las Vegas NV USACenter of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USACenter of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USACenter of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USACenter for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USAAbstract SARS‐CoV‐2 acute respiratory distress syndrome (ARDS) induces uncontrolled lung inflammation and coagulopathy with high mortality. Anti‐viral drugs and monoclonal antibodies reduce early COVID‐19 severity, but treatments for late‐stage immuno‐thrombotic syndromes and long COVID are limited. Serine protease inhibitors (SERPINS) regulate activated proteases. The myxoma virus‐derived Serp‐1 protein is a secreted immunomodulatory serpin that targets activated thrombotic, thrombolytic, and complement proteases as a self‐defense strategy to combat clearance. Serp‐1 is effective in multiple animal models of inflammatory lung disease and vasculitis. Here, we describe systemic treatment with purified PEGylated Serp‐1 as a therapy for immuno‐coagulopathic complications during ARDS. Treatment with PEGSerp‐1 in two mouse‐adapted SARS‐CoV‐2 models in C57Bl/6 and BALB/c mice reduced lung and heart inflammation, with improved outcomes. PEGSerp‐1 significantly reduced M1 macrophages in the lung and heart by modifying urokinase‐type plasminogen activator receptor (uPAR), thrombotic proteases, and complement membrane attack complex (MAC). Sequential changes in gene expression for uPAR and serpins (complement and plasminogen inhibitors) were observed. PEGSerp‐1 is a highly effective immune‐modulator with therapeutic potential for severe viral ARDS, immuno‐coagulopathic responses, and Long COVID.https://doi.org/10.15252/emmm.202317376complementinflammationSARS‐CoV‐2serpinuPAR |
| spellingShingle | Liqiang Zhang Yize (Henry) Li Karen Kibler Simona Kraberger Arvind Varsani Julie Turk Nora Elmadbouly Emily Aliskevich Laurel Spaccarelli Bereket Estifanos Junior Enow Isabela Rivabem Zanetti Nicholas Saldevar Efrem Lim Jessika Schlievert Kyle Browder Anjali Wilson Fernando Arcos Juan Aubrey Pinteric Aman Garg Henna Monder Rohan Saju Savanah Gisriel Bertram Jacobs Timothy L Karr Esther Borges Florsheim Vivek Kumar John Wallen Masmudur Rahman Grant McFadden Brenda G Hogue Alexandra R Lucas Viral anti‐inflammatory serpin reduces immuno‐coagulopathic pathology in SARS‐CoV‐2 mouse models of infection EMBO Molecular Medicine complement inflammation SARS‐CoV‐2 serpin uPAR |
| title | Viral anti‐inflammatory serpin reduces immuno‐coagulopathic pathology in SARS‐CoV‐2 mouse models of infection |
| title_full | Viral anti‐inflammatory serpin reduces immuno‐coagulopathic pathology in SARS‐CoV‐2 mouse models of infection |
| title_fullStr | Viral anti‐inflammatory serpin reduces immuno‐coagulopathic pathology in SARS‐CoV‐2 mouse models of infection |
| title_full_unstemmed | Viral anti‐inflammatory serpin reduces immuno‐coagulopathic pathology in SARS‐CoV‐2 mouse models of infection |
| title_short | Viral anti‐inflammatory serpin reduces immuno‐coagulopathic pathology in SARS‐CoV‐2 mouse models of infection |
| title_sort | viral anti inflammatory serpin reduces immuno coagulopathic pathology in sars cov 2 mouse models of infection |
| topic | complement inflammation SARS‐CoV‐2 serpin uPAR |
| url | https://doi.org/10.15252/emmm.202317376 |
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