Dengue Virus Infection of Primary Endothelial Cells Induces Innate Immune Responses, Changes in Endothelial Cells Function and Is Restricted by Interferon-Stimulated Responses

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Calvert, Julie K
Helbig, K J
Dimasi, David Paul
Cockshell, M
Beard, Michael
Pitson, S M
Bonder, Claudine
Carr, Jill
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Mary Ann Liebert, Inc.
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.
This is a peer reviewed post print version, the final publication is available from Mary Ann Liebert, Inc., publishers A 12 month embargo from date of publication has been placed on this article in accordance with the publishers self-archiving policy. The article will be available from 6 August 2016.
Calvert JK, Helbig KJ, Dimasi D, Cockshell M, Beard MR, Pitson SM, Bonder CS, Carr JM. Dengue Virus Infection of Primary Endothelial Cells Induces InnateImmune Responses, Changes in Endothelial Cells Function and Is Restricted byInterferon-Stimulated Responses. Journal of Interferon and Cytokine Research . 2015 Aug;35(8):654-65. doi: 10.1089/jir.2014.0195.