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

Luplerdlop, N.; Misse, D.; Bray, D.; Deleuze, V.; Gonzalez, J. P.; Leardkamolkarn, V.; Yssel, H.; Veas, F.

EMBO Reports

2006-11 / vol 7 / pages 1176-1181


Dengue virus (DV) is an important re-emerging arthropod-borne virus of global significance. The defining characteristic of DV infection-associated pathology is haernorrhagic 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 enclothelial 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 enclothelial 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 haernorrhagic fever-inducing viruses, and identify a new therapeutic approach for the treatment of viral-induced vascular leakage by specifically targeting gelatinolytic metal loproteases.



activation; alpha-converting enzyme; endothelial cells; expression; haemorrhagic fever viruses; hemorrhagic-fever; interleukin-8; matrix metalloprotease inhibitors; matrix metalloproteinases; matrix-metalloproteinase-9; mmp-9; pathogenesis; permeability; plasma leakage; sb-3ct

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