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Myxomavirus-Derived Serpin Prolongs Survival and Reduces Inflammation and Hemorrhage in an Unrelated Lethal Mouse Viral Infection
- Publication Year :
- 2013
- Publisher :
- American Society for Microbiology, 2013.
-
Abstract
- Lethal viral infections produce widespread inflammation with vascular leak, clotting, and bleeding (disseminated intravascular coagulation [DIC]), organ failure, and high mortality. Serine proteases in clot-forming (thrombotic) and clot-dissolving (thrombolytic) cascades are activated by an inflammatory cytokine storm and also can induce systemic inflammation with loss of normal ser ine p rotease in hibitor (serpin) regulation. Myxomavirus secretes a potent anti-inflammatory serpin, Serp-1, that inhibits clotting factor X (fX) and thrombolytic tissue- and urokinase-type plasminogen activators (tPA and uPA) with anti-inflammatory activity in multiple animal models. Purified serpin significantly improved survival in a murine gammaherpesvirus 68 (MHV68) infection in gamma interferon receptor (IFN-γR) knockout mice, a model for lethal inflammatory vasculitis. Treatment of MHV68-infected mice with neuroserpin, a mammalian serpin that inhibits only tPA and uPA, was ineffective. Serp-1 reduced virus load, lung hemorrhage, and aortic, lung, and colon inflammation in MHV68-infected mice and also reduced virus load. Neuroserpin suppressed a wide range of immune spleen cell responses after MHV68 infection, while Serp-1 selectively increased CD11c + splenocytes (macrophage and dendritic cells) and reduced CD11b + tissue macrophages. Serp-1 altered gene expression for coagulation and inflammatory responses, whereas neuroserpin did not. Serp-1 treatment was assessed in a second viral infection, mouse-adapted Zaire ebolavirus in wild-type BALB/c mice, with improved survival and reduced tissue necrosis. In summary, treatment with this unique myxomavirus-derived serpin suppresses systemic serine protease and innate immune responses caused by unrelated lethal viral infections (both RNA and DNA viruses), providing a potential new therapeutic approach for treatment of lethal viral sepsis.
- Subjects :
- Vasculitis
Proteases
Inflammation
Hemorrhage
Serpin
Biology
Systemic inflammation
Antiviral Agents
Interferon-gamma
Mice
Gammaherpesvirinae
Neuroserpin
medicine
Animals
Pharmacology (medical)
Serpins
Pharmacology
Disseminated intravascular coagulation
Clotting factor
Mice, Knockout
Mice, Inbred BALB C
Innate immune system
Macrophages
Neuropeptides
Myxoma virus
Membrane Proteins
Dendritic Cells
Herpesviridae Infections
Hemorrhagic Fever, Ebola
medicine.disease
Ebolavirus
Survival Analysis
Urokinase-Type Plasminogen Activator
Disease Models, Animal
Infectious Diseases
Tissue Plasminogen Activator
Immunology
Factor X
medicine.symptom
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....8663600d954503394b04c8fc5e21e118