Dengue Virus infection of primary endothelial cells induces innate immune responses, changes in endothelial cells function and is restricted by Interferon-stimulated responses

Julie Calvert, Karla Helbig, David Dimasi, Michaelia Cockshell, Michael Beard, Stuart Pitson, C Bonder, Jillian Carr

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    20 Citations (Scopus)

    Abstract

    Although endothelial cell (EC) infection is not widespread during dengue virus (DENV) infection in vivo, the endothelium is the site of the pathogenic effects seen in severe DENV disease. In this study, we investigated DENV infection of primary EC and defined factors that influence infection in this cell type. Consistent with in vivo findings where EC infection is infrequent, only 3%-15% of EC became productively DENV-2-infected in vitro. This low level infection could not be attributed to inhibition by heparin, EC donor variation, heterogeneity, or biological source. DENV-infection of EC was associated with induction of innate immune responses, including increased STAT1 protein, STAT1-phosphorylation, interferon (IFN)-β, OAS-1, IFIT-1/ISG56, and viperin mRNA. Antibody blocking of IFN-β inhibited the induction of OAS1, IFIT1/ISG56, and viperin while shRNA knockdown of viperin enhanced DENV-infection in EC. DENV-infection of EC resulted in increased activity of sphingosine kinase 1, a factor important in maintaining vascular integrity, and altered basal and stimulated changes in barrier integrity of DENV-infected EC monolayers. Thus, DENV productively infects only a small percentage of primary EC but this has a major influence on induction of IFN-β driven innate immune responses that can restrict infection while the EC themselves are functionally altered. These changes may have important consequences for the endothelium and are reflective of pathogenic changes associated with vascular leakage, as seen in DENV disease.

    Original languageEnglish
    Pages (from-to)654-665
    Number of pages12
    JournalJournal of Interferon and Cytokine Research
    Volume35
    Issue number8
    DOIs
    Publication statusPublished - 1 Aug 2015

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