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Antimicrob Agents Chemother. Myxomavirus-Derived Serpin Prolongs Survival and Reduces Inflammation and Hemorrhage in an Unrelated Lethal Mouse Viral Infection
[Source: Antimicrobial Agents Chemotherapy, full page: (LINK). Abstract, edited.]
Myxomavirus-Derived Serpin Prolongs Survival and Reduces Inflammation and Hemorrhage in an Unrelated Lethal Mouse Viral Infection
Hao Chen <SUP>a</SUP>,<SUP>b</SUP>, Donghang Zheng <SUP>a</SUP>,<SUP>b</SUP>, Jeff Abbott<SUP>c</SUP>, Liying Liu <SUP>a</SUP>, Mee Y. Bartee <SUP>a</SUP>,<SUP>b</SUP>, Maureen Long <SUP>c</SUP>, Jennifer Davids <SUP>a</SUP>,<SUP>b</SUP>, Jennifer Williams <SUP>a</SUP>, Heinz Feldmann <SUP>d</SUP>*, James Strong<SUP>d</SUP>, Katrina R. Grau<SUP>b</SUP>,Scott Tibbetts<SUP>b</SUP>, Colin Macaulay<SUP>e</SUP>, Grant McFadden <SUP>b</SUP>,<SUP>e</SUP>, Robert Thoburn <SUP>a</SUP>, David A. Lomas <SUP>f</SUP>,Francis G. Spinale <SUP>g</SUP>, Herbert W. Virgin<SUP>h</SUP> and Alexandra Lucas <SUP>a</SUP>,<SUP>b</SUP>,<SUP>e</SUP>
<SUP></SUP>
Author Affiliations: Divisions of Cardiology and Rheumatology, Department of Medicine<SUP>a </SUP>Department of Molecular Genetics and Microbiology<SUP>b </SUP>College of Veterinary Medicine,<SUP>c</SUP> University of Florida, Gainesville, Florida, USA National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada<SUP>d </SUP>Viron Therapeutics, Inc., London, Ontario, Canada<SUP>e</SUP>Division of Pulmonary Medicine, Department of Medicine, University of Cambridge, Cambridge, United Kingdom<SUP>f </SUP>Department of Surgery, Medical University of South Carolina, Department of Cell Biology and Anatomy, South Carolina, USA<SUP>g </SUP>Departments of Pathology and Immunology and Molecular Microbiology, Washington University, St Louis, Missouri, USA<SUP>h</SUP>
<SUP></SUP>
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 normalserine protease inhibitor (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<SUP>+</SUP> splenocytes (macrophage and dendritic cells) and reduced CD11b<SUP>+</SUP> 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.
FOOTNOTES
Received 17 January 2013. Returned for modification 21 February 2013. Accepted 30 May 2013.
Address correspondence to Alexandra Lucas,alexandra.lucas@medicine.ufl.edu.
* Present address: Heinz Feldmann, Laboratory of Virology, Division of Intramural Research (DIR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rocky Mountain Laboratories, Hamilton, Montana, USA.
Published ahead of print 17 June 2013
Supplemental material for this article may be found at http://dx.doi.org/10.1128/AAC.02594-12.
Copyright ? 2013, American Society for Microbiology. All Rights Reserved
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Myxomavirus-Derived Serpin Prolongs Survival and Reduces Inflammation and Hemorrhage in an Unrelated Lethal Mouse Viral Infection
Hao Chen <SUP>a</SUP>,<SUP>b</SUP>, Donghang Zheng <SUP>a</SUP>,<SUP>b</SUP>, Jeff Abbott<SUP>c</SUP>, Liying Liu <SUP>a</SUP>, Mee Y. Bartee <SUP>a</SUP>,<SUP>b</SUP>, Maureen Long <SUP>c</SUP>, Jennifer Davids <SUP>a</SUP>,<SUP>b</SUP>, Jennifer Williams <SUP>a</SUP>, Heinz Feldmann <SUP>d</SUP>*, James Strong<SUP>d</SUP>, Katrina R. Grau<SUP>b</SUP>,Scott Tibbetts<SUP>b</SUP>, Colin Macaulay<SUP>e</SUP>, Grant McFadden <SUP>b</SUP>,<SUP>e</SUP>, Robert Thoburn <SUP>a</SUP>, David A. Lomas <SUP>f</SUP>,Francis G. Spinale <SUP>g</SUP>, Herbert W. Virgin<SUP>h</SUP> and Alexandra Lucas <SUP>a</SUP>,<SUP>b</SUP>,<SUP>e</SUP>
<SUP></SUP>
Author Affiliations: Divisions of Cardiology and Rheumatology, Department of Medicine<SUP>a </SUP>Department of Molecular Genetics and Microbiology<SUP>b </SUP>College of Veterinary Medicine,<SUP>c</SUP> University of Florida, Gainesville, Florida, USA National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada<SUP>d </SUP>Viron Therapeutics, Inc., London, Ontario, Canada<SUP>e</SUP>Division of Pulmonary Medicine, Department of Medicine, University of Cambridge, Cambridge, United Kingdom<SUP>f </SUP>Department of Surgery, Medical University of South Carolina, Department of Cell Biology and Anatomy, South Carolina, USA<SUP>g </SUP>Departments of Pathology and Immunology and Molecular Microbiology, Washington University, St Louis, Missouri, USA<SUP>h</SUP>
<SUP></SUP>
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 normalserine protease inhibitor (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<SUP>+</SUP> splenocytes (macrophage and dendritic cells) and reduced CD11b<SUP>+</SUP> 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.
FOOTNOTES
Received 17 January 2013. Returned for modification 21 February 2013. Accepted 30 May 2013.
Address correspondence to Alexandra Lucas,alexandra.lucas@medicine.ufl.edu.
* Present address: Heinz Feldmann, Laboratory of Virology, Division of Intramural Research (DIR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rocky Mountain Laboratories, Hamilton, Montana, USA.
Published ahead of print 17 June 2013
Supplemental material for this article may be found at http://dx.doi.org/10.1128/AAC.02594-12.
Copyright ? 2013, American Society for Microbiology. All Rights Reserved
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