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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 and Chemotherapy, full text: (LINK). Abstract, edited.]
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Myxomavirus-derived Serpin Prolongs Survival and Reduces Inflammation and Hemorrhage in an Unrelated Lethal Mouse Viral Infection [PublishAheadOfPrint]
Chen, H., Zheng, D., Abbott, J., Liu, L., Bartee, M. Y., Long, M., Davids, J., Williams, J., Feldmann, H., Strong, J., Grau, K. R., Tibbetts, S., Macaulay, C., McFadden, G., Thoburn, R., Lomas, D. A., Spinale, F. G., Virgin, H. W., Lucas, A.
Abstract
Lethal viral infections produce widespread inflammation with vascular leak, clotting and bleeding (disseminated intravascular coagulation, termed 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, uPA) with anti-inflammatory activity in multiple animal models. Purified serpin significantly improved survival in a murine Gammaherpesvirus-68 (MHV68) infection in interferon gamma receptor (IFNR) knock-out mice, a model for lethal inflammatory vascultis. 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 macrophage. 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.
-Chen, H., Zheng, D., Abbott, J., Liu, L., Bartee, M. Y., Long, M., Davids, J., Williams, J., Feldmann, H., Strong, J., Grau, K. R., Tibbetts, S., Macaulay, C., McFadden, G., Thoburn, R., Lomas, D. A., Spinale, F. G., Virgin, H. W., Lucas, A.
Abstract
Lethal viral infections produce widespread inflammation with vascular leak, clotting and bleeding (disseminated intravascular coagulation, termed 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, uPA) with anti-inflammatory activity in multiple animal models. Purified serpin significantly improved survival in a murine Gammaherpesvirus-68 (MHV68) infection in interferon gamma receptor (IFNR) knock-out mice, a model for lethal inflammatory vascultis. 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 macrophage. 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.
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