Dengue-virus-infected dendritic cells trigger vascular leakage through metalloproteinase overproduction

• Published in: EMBO reports 2006-11, Vol.7 (11), p.1176-1181
• Main Authors: Luplerdlop, Natthanej, Missé, Dorothée, Bray, Dorothy, Deleuze, Virginie, Gonzalez, Jean-Paul, Leardkamolkarn, Vijittra, Yssel, Hans, Veas, Francisco
• Format: Article
• Language: English
• Subjects: Adhesion; Capillary Permeability; Cells, Cultured; Circulatory system; Culture Media, Conditioned - pharmacology; Dendritic Cells - immunology; Dendritic Cells - virology; Dengue virus; Dengue Virus - immunology; EMBO24; endothelial cells; Endothelium, Vascular - immunology; Endothelium, Vascular - virology; Fever; Fibers; haemorrhagic fever viruses; Hemorrhage; Humans; Life Sciences; matrix metalloprotease inhibitors; Medical treatment; Metalloproteases - antagonists & inhibitors; Metalloproteases - metabolism; Molecular biology; Pathology; Permeability; plasma leakage; SB-3CT; Scientific Report; Severe Dengue - complications; Severe Dengue - immunology; Severe Dengue - metabolism; Syndrome; Vector-borne diseases; Virology
• ISSN: 1469-221X; 1469-3178; 1469-221X
• DOI: 10.1038/sj.embor.7400814

Dengue virus (DV) is an important re‐emerging arthropod‐borne virus of global significance. The defining characteristic of DV infection‐associated pathology is haemorrhagic fever, which often leads to a fatal shock‐like syndrome (DHF/DSS) owing to an increase in vascular endothelial permeability. Here, we show, in a viral dose‐dependent manner, that DV‐infected immature dendritic cells overproduce soluble gelatinolytic matrix metalloproteinase (MMP)‐9—and to a lesser extent MMP‐2—which enhances endothelial permeability, but which are reduced by specific inhibitors and a neutralizing anti‐MMP‐9 antibody. This permeability was associated with a loss of expression of the platelet endothelial adhesion molecule 1 (PECAM‐1) and vascular endothelium (VE)‐cadherin cell adhesion molecules and redistribution of F‐actin fibres. These in vitro observations were confirmed in an in vivo vascular‐leakage mouse model. These results provide a molecular basis for DHF/DSS that could be a basis for a general model of haemorrhagic fever‐inducing viruses, and identify a new therapeutic approach for the treatment of viral‐induced vascular leakage by specifically targeting gelatinolytic metalloproteases.