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.
Synopsis image Here we examined a virus‐derived immune modulating serpin, PEGSerp‐1, as a treatment for severe viral infection. Later stage inflammatory and coagulation (thrombotic and thrombolytic) pathway activity cause prolonged disease. This is a new class of virus‐derived immune‐modulating protein biologic. Both early prophylactic and late delayed serpin treatment improved clinical score and weight in a mouse SARS‐CoV‐2 infection. PEGSerp‐1 consistently reduced inflammatory macrophage invasion in both C57Bl/6 and BALB/c mouse models. Improved clinical findings and reduced inflammation with PEGSerp‐1 treatment correlated with reduced uPAR and complement on IHC stained tissue, and elevated mammalian uPAR and increased mammalian serpin gene expression in lung and heart.