Myxomavirus-derived serpin prolongs survival and reduces inflammation and hemorrhage in an unrelated lethal mouse viral infection

Antimicrob Agents Chemother. 2013 Sep;57(9):4114-27. doi: 10.1128/AAC.02594-12. Epub 2013 Jun 17.

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 serine 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(+) 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism
  • Dendritic Cells / pathology
  • Disease Models, Animal
  • Ebolavirus
  • Factor X / antagonists & inhibitors
  • Factor X / metabolism
  • Gammaherpesvirinae
  • Hemorrhage / drug therapy*
  • Hemorrhage / mortality
  • Hemorrhage / pathology
  • Hemorrhage / virology
  • Hemorrhagic Fever, Ebola / drug therapy*
  • Hemorrhagic Fever, Ebola / mortality
  • Hemorrhagic Fever, Ebola / pathology
  • Hemorrhagic Fever, Ebola / virology
  • Herpesviridae Infections / drug therapy*
  • Herpesviridae Infections / mortality*
  • Herpesviridae Infections / pathology
  • Herpesviridae Infections / virology
  • Inflammation / drug therapy
  • Inflammation / mortality
  • Inflammation / pathology
  • Inflammation / virology
  • Interferon-gamma / deficiency
  • Interferon-gamma / genetics
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Macrophages / pathology
  • Membrane Proteins / isolation & purification
  • Membrane Proteins / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Myxoma virus / chemistry*
  • Myxoma virus / physiology
  • Neuropeptides / pharmacology
  • Serpins / pharmacology
  • Survival Analysis
  • Tissue Plasminogen Activator / antagonists & inhibitors
  • Tissue Plasminogen Activator / metabolism
  • Urokinase-Type Plasminogen Activator / antagonists & inhibitors
  • Urokinase-Type Plasminogen Activator / metabolism
  • Vasculitis / drug therapy
  • Vasculitis / mortality
  • Vasculitis / pathology
  • Vasculitis / virology

Substances

  • Membrane Proteins
  • Neuropeptides
  • Serp1 protein, mouse
  • Serpins
  • neuroserpin
  • Interferon-gamma
  • Factor X
  • Tissue Plasminogen Activator
  • Urokinase-Type Plasminogen Activator