Broad antiviral activity of carbohydrate-binding agents against the four serotypes of dengue virus in monocyte-derived dendritic cells.

Johan K Sandberg,Marijke M F Alen,Dominique Schols,Tine De Burghgraeve,Jan Balzarini,Suzanne J F Kaptein,Johan Neyts

doi:10.1371/journal.pone.0021658

Abstract

BackgroundDendritic cells (DC), present in the skin, are the first target cells of dengue virus (DENV). Dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) is present on DC and recognizes N-glycosylation sites on the E-glycoprotein of DENV. Thus, the DC-SIGN/E-glycoprotein interaction can be considered as an important target for inhibitors of viral replication. We evaluated various carbohydrate-binding agents (CBAs) against all four described serotypes of DENV replication in Raji/DC-SIGN+ cells and in monocyte-derived DC (MDDC).Methodology/Principal FindingsA dose-dependent anti-DENV activity of the CBAs Hippeastrum hybrid (HHA), Galanthus nivalis (GNA) and Urtica dioica (UDA), but not actinohivin (AH) was observed against all four DENV serotypes as analyzed by flow cytometry making use of anti-DENV antibodies. Remarkably, the potency of the CBAs against DENV in MDDC cultures was significantly higher (up to 100-fold) than in Raji/DC-SIGN+ cells. Pradimicin-S (PRM-S), a small-size non-peptidic CBA, exerted antiviral activity in MDDC but not in Raji/DC-SIGN+ cells. The CBAs act at an early step of DENV infection as they bind to the viral envelope of DENV and subsequently prevent virus attachment. Only weak antiviral activity of the CBAs was detected when administered after the virus attachment step. The CBAs were also able to completely prevent the cellular activation and differentiation process of MDDC induced upon DENV infection.Conclusions/SignificanceThe CBAs exerted broad spectrum antiviral activity against the four DENV serotypes, laboratory-adapted viruses and low passage clinical isolates, evaluated in Raji/DC-SIGN+ cells and in primary MDDC.

Highlights

Dengue virus (DENV) belongs to the family of the Flaviviridae and is the most important emerging mosquito-borne virus in tropical and subtropical countries
The four DENV serotypes used in our experiments were grown in the insect cell line C6/36 to mimic the first encounter of the Dendritic cells (DC) with DENV
DENV-infected DC and macrophages play a key role in the immunopathogenesis of dengue hemorrhagic fever by the production of proinflammatory cytokines, chemokines, metalloproteinases and the induction of cell maturation [37,38]

Summary

Introduction

Dengue virus (DENV) belongs to the family of the Flaviviridae and is the most important emerging mosquito-borne virus in tropical and subtropical countries. After infection with a second different serotype, the cross-reacting non-neutralizing antibodies against the first serotype will recognize the heterologous virus and enhance DENV access to Fc-receptor bearing cells [2]. This phenomenon is called antibodydependent enhancement (ADE) and leads to a higher viremia, increased vascular permeability and a severe hemorrhagic disease [3,4,5,6]. Reasons for the spread of dengue virus are the expansion of global population and travelling, deforestation, solid waste systems and poor vector control. We evaluated various carbohydrate-binding agents (CBAs) against all four described serotypes of DENV replication in Raji/DC-SIGN+ cells and in monocyte-derived DC (MDDC)

Methods

Results

Conclusion