title: Myxomavirus-derived serpin prolongs survival and reduces inflammation and hemorrhage in an unrelated lethal mouse viral infection.
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.
authors.affiliation: Divisions of Cardiology and Rheumatology, Department of Medicine, University of Florida, Gainesville, Florida, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.forename: Donghang
authors.initials: D
authors.lastname: Zheng
authors.forename: Jeff
authors.initials: J
authors.lastname: Abbott
authors.forename: Liying
authors.initials: L
authors.lastname: Liu
authors.forename: Mee Y
authors.initials: MY
authors.lastname: Bartee
authors.forename: Maureen
authors.initials: M
authors.lastname: Long
authors.forename: Jennifer
authors.initials: J
authors.lastname: Davids
authors.forename: Jennifer
authors.initials: J
authors.lastname: Williams
authors.forename: Heinz
authors.initials: H
authors.lastname: Feldmann
authors.forename: James
authors.initials: J
authors.lastname: Strong
authors.forename: Katrina R
authors.initials: KR
authors.lastname: Grau
authors.forename: Scott
authors.initials: S
authors.lastname: Tibbetts
authors.forename: Colin
authors.initials: C
authors.lastname: Macaulay
authors.forename: Grant
authors.initials: G
authors.lastname: McFadden
authors.forename: Robert
authors.initials: R
authors.lastname: Thoburn
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lucas
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D029043:Ebolavirus; D005170:Factor X / Q000037:antagonists & inhibitors / Q000378:metabolism; D018142:Gammaherpesvirinae; D006470:Hemorrhage / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000821:virology; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000821:virology; D006566:Herpesviridae Infections / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology / Q000821:virology; D007249:Inflammation / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000821:virology; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000302:isolation & purification / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009233:Myxoma virus / Q000737:chemistry* / Q000502:physiology; D009479:Neuropeptides / Q000494:pharmacology; D015843:Serpins / Q000494:pharmacology; D016019:Survival Analysis; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors / Q000378:metabolism; D014657:Vasculitis / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000821:virology; D000097522:Neuroserpin
chemical_list: D005170:Factor X; D007371:Interferon-gamma; D008565:Membrane Proteins; D009479:Neuropeptides; D015843:Serpins; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D000097522:Neuroserpin; C511174:Serp1 protein, mouse