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

Hao Chen, Donghang Zheng, Jeff Abbott, Liying Liu, Mee Y. Bartee, Maureen Long, Jennifer Davids, Jennifer Williams, Heinz Feldmann, James Strong, Katrina R. Grau, Scott Tibbetts, Colin Macaulay, Grant McFadden, Robert Thoburn, David A. Lomas, Francis G. Spinale, Herbert W. Virgin, Alexandra Lucas

Research output: Contribution to journalArticle

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4114-4127
Number of pages14
JournalAntimicrobial Agents and Chemotherapy
Volume57
Issue number9
DOIs
StatePublished - Sep 1 2013
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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    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. (2013). Myxomavirus-derived serpin prolongs survival and reduces inflammation and hemorrhage in an unrelated lethal mouse viral infection. Antimicrobial Agents and Chemotherapy, 57(9), 4114-4127. https://doi.org/10.1128/AAC.02594-12