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Treatment with anti-inflammatory viral serpin modulates immuno-thrombotic responses and improves outcomes in SARS-CoV-2 infected mice (preprint)
biorxiv; 2022.
Preprint
in English
| bioRxiv | ID: ppzbmed-10.1101.2022.09.09.507363
ABSTRACT
Severe acute respiratory distress syndrome (ARDS) during SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) infection, manifests as uncontrolled lung inflammation and systemic thrombosis with high mortality. Anti-viral drugs and monoclonal antibodies can reduce COVID-19 severity if administered in the early viremic phase, but treatments for later stage immuno-thrombotic syndrome and long COVID are limited. Serine protease inhibitors (SERPINS) regulate activated proteases during thrombotic, thrombolytic and immune responses. The myxoma poxvirus-derived Serp-1 protein is a secreted immunomodulatory serpin that targets activated coagulation and complement protease pathways as part of a self-defense strategy to combat viral clearance by the innate immune system. When purified and utilized as an anti-immune therapeutic, Serp-1 is effective as an anti-inflammatory drug in multiple animal models of inflammatory lung disease and vasculitis. Here, we describe systemic treatment with purified PEGylated Serp-1 (PEGSerp-1) as a therapy for immuno-thrombotic complications during ARDS. Treatment with PEGSerp-1 in two distinct mouse-adapted SARS-CoV-2 models in C57Bl/6 and BALB/c mice reduced lung and heart inflammation, with improved clinical outcomes. PEGSerp-1 significantly reduced M1 macrophage invasion in the lung and heart by modifying urokinase-type plasminogen activator receptor (uPAR) and complement membrane attack complex (MAC). Sequential changes in urokinase-type plasminogen activator receptor (uPAR) and serpin gene expression were observed in lung and heart with PEGSerp-1 treatment. PEGSerp-1 is a highly effective immune-modulator with therapeutic potential for treatment of severe viral ARDS with additional potential to reduce late SARS-CoV-2 complications related to immune-thrombotic events that persist during long COVID. Significance:
Severe acute respiratory distress syndrome (ARDS) in SARS-CoV-2 infection manifests as uncontrolled tissue inflammation and systemic thrombosis with high mortality. Anti-viral drugs and monoclonal antibodies reduce COVID-19 severity if administered early, but treatments for later stage immuno-thrombosis are limited. Serine protease inhibitors (SERPINS) regulate thrombotic, thrombolytic and complement pathways. We investigate here systemic treatment with purified poxvirus-derived PEGSerp-1 as a therapeutic for immuno-thrombotic complications in viral ARDS. PEGSerp-1 treatment in two mouse-adapted SARS-CoV-2 models (C57Bl/6 and BALB/c) significantly reduced lung and heart inflammation and improved clinical outcomes, with sequential changes in thrombolytic (uPAR) and complement expression. PEGSerp-1 is a highly effective immune-modulator with therapeutic potential for immune-thrombotic complications in severe viral ARDS and has potential benefit for long COVID.
Full text:
Available
Collection:
Preprints
Database:
bioRxiv
Main subject:
Pneumonia
/
Respiratory Distress Syndrome
/
Thrombosis
/
Vasculitis
/
Acquired Immunodeficiency Syndrome
/
Coronavirus Infections
/
Blood Coagulation Disorders, Inherited
/
Severe Acute Respiratory Syndrome
/
COVID-19
/
Inflammation
Language:
English
Year:
2022
Document Type:
Preprint
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