Dendritic Cell-specific Intercellular Adhesion Molecule 3-grabbing Non-integrin (DC-SIGN)-mediated Enhancement of Dengue Virus Infection Is Independent of DC-SIGN Internalization Signals

Jean-Louis Virelizier,Isabelle Staropoli,Ali Amara,Philippe Desprès,Laura Burleigh,Fernando Arenzana-Seisdedos,Julie Harriague,Erika Navarro-Sanchez,Felix A. Rey,Pierre-Yves Lozach

doi:10.1074/jbc.m504337200

Abstract

Dengue virus (DV) is a mosquito-borne flavivirus that causes hemorrhagic fever in humans. In the natural infection, DV is introduced into human skin by an infected mosquito vector where it is believed to target immature dendritic cells (DCs) and Langerhans cells (LCs). We found that DV productively infects DCs but not LCs. We show here that the interactions between DV E protein, the sole mannosylated glycoprotein present on DV particles, and the C-type lectin dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) are essential for DV infection of DCs. Binding of mannosylated N-glycans on DV E protein to DC-SIGN triggers a rapid and efficient internalization of the viral glycoprotein. However, we observed that endocytosis-defective DC-SIGN molecules allow efficient DV replication, indicating that DC-SIGN endocytosis is dispensable for the internalization step in DV entry. Together, these results argue in favor of a mechanism by which DC-SIGN enhances DV entry and infection in cis. We propose that DC-SIGN concentrates mosquito-derived DV particles at the cell surface to allow efficient interaction with an as yet unidentified entry factor that is ultimately responsible for DV internalization and pH-dependent fusion into DCs.

Highlights

Dengue virus (DV)1 is an arthropod-borne flavivirus that belongs to the Flaviviridae family (1)
Immature dendritic cells (DCs) and Langerhans cells (LCs), which are normally resident in the skin, have been shown to be infected by DV and are believed to be the first cells targeted by the virus (4)
To determine whether each cell type displays the characteristic phenotype of DCs and LCs, cells were stained for expression of CD1a, dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN), and Langerin, a C-type lectin selectively expressed by LCs and involved in the formation of a LC-specific organelle, the Birbeck granule (26 –28)

Summary

Introduction

Dengue virus (DV)1 is an arthropod-borne flavivirus that belongs to the Flaviviridae family (1). To evaluate whether this activation process requires DC-SIGN-mediated viral infection, we challenged immature DCs with DV-1 FGA/NA d1d at an m.o.i. of 5, in the presence or absence of anti-DC-SIGN mAb or isotype control Ab. At 40 h post-infection, cell surface expression of CD83 and CD86, two DC maturation markers, was evaluated by flow cytometry (Fig. 2D).

Results

Conclusion