EMBO Molecular Medicine (Sep 2023)
Viral anti‐inflammatory serpin reduces immuno‐coagulopathic pathology in SARS‐CoV‐2 mouse models of infection
- 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
Affiliations
- Liqiang Zhang
- Center for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USA
- Yize (Henry) Li
- Center of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USA
- Karen Kibler
- Center of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USA
- Simona Kraberger
- Center of Fundamental and Applied Microbiomics Biodesign Institute, Arizona State University Tempe AZ USA
- Arvind Varsani
- School of Life Sciences Arizona State University Tempe AZ USA
- Julie Turk
- Center for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USA
- Nora Elmadbouly
- Center for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USA
- Emily Aliskevich
- Center for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USA
- Laurel Spaccarelli
- Center for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USA
- Bereket Estifanos
- Center of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USA
- Junior Enow
- Center of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USA
- Isabela Rivabem Zanetti
- Center for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USA
- Nicholas Saldevar
- Center for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USA
- Efrem Lim
- School of Life Sciences Arizona State University Tempe AZ USA
- Jessika Schlievert
- Center of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USA
- Kyle Browder
- Center for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USA
- Anjali Wilson
- Center of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USA
- Fernando Arcos Juan
- Center of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USA
- Aubrey Pinteric
- Center for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USA
- Aman Garg
- Center for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USA
- Henna Monder
- Center for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USA
- Rohan Saju
- Center for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USA
- Savanah Gisriel
- Center for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USA
- Bertram Jacobs
- Center of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USA
- Timothy L Karr
- Center for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USA
- Esther Borges Florsheim
- Center of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USA
- Vivek Kumar
- New Jersey Institute of Technology Newark NJ USA
- John Wallen
- Colt Advisors LLC Las Vegas NV USA
- Masmudur Rahman
- Center of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USA
- Grant McFadden
- Center of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USA
- Brenda G Hogue
- Center of Immunotherapy, Vaccines and Virotherapy, Biodesign Institute Arizona State University Tempe AZ USA
- Alexandra R Lucas
- Center for Personalized Diagnostics, Biodesign Institute Arizona State University Tempe AZ USA
- DOI
- https://doi.org/10.15252/emmm.202317376
- Journal volume & issue
-
Vol. 15,
no. 9
pp. n/a – n/a
Abstract
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.
Keywords