Viral anti-inflammatory serpin reduces immuno-coagulopathic pathology in SARS-CoV-2 mouse models of infection

Liqiang Zhang, Yize 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 GargHenna 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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Article numbere17376
JournalEMBO Molecular Medicine
Volume15
Issue number9
DOIs
StatePublished - Sep 11 2023

All Science Journal Classification (ASJC) codes

  • Molecular Medicine

Keywords

  • SARS-CoV-2
  • complement
  • inflammation
  • serpin
  • uPAR

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