Viral anti‐inflammatory serpin reduces immuno‐coagulopathic pathology in <scp>SARS‐CoV</scp>‐2 mouse models of infection
Category
Published on
Type
journal-article
Author
Liqiang Zhang and Yize (Henry) Li and Karen Kibler and Simona Kraberger and Arvind Varsani and Julie Turk and Nora Elmadbouly and Emily Aliskevich and Laurel Spaccarelli and Bereket Estifanos and Junior Enow and Isabela Rivabem Zanetti and Nicholas Saldevar and Efrem Lim and Jessika Schlievert and Kyle Browder and Anjali Wilson and Fernando Arcos Juan and Aubrey Pinteric and Aman Garg and Henna Monder and Rohan Saju and Savanah Gisriel and Bertram Jacobs and Timothy L Karr and Esther Borges Florsheim and Vivek Kumar and John Wallen and Masmudur Rahman and Grant McFadden and Brenda G Hogue and Alexandra R Lucas
Citation
Zhang, L., Li, Y. (Henry), Kibler, K., Kraberger, S., Varsani, A., Turk, J., Elmadbouly, N., Aliskevich, E., Spaccarelli, L., Estifanos, B., Enow, J., Zanetti, I. R., Saldevar, N., Lim, E., Schlievert, J., Browder, K., Wilson, A., Juan, F. A., Pinteric, A., … Lucas, A. R. (2023). Viral anti‐inflammatory serpin reduces immuno‐coagulopathic pathology in SARS‐CoV ‐2 mouse models of infection. EMBO Molecular Medicine, 15(9). Portico. https://doi.org/10.15252/emmm.202317376
Abstract
AbstractSARS‐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.
