title: Dengue-virus-infected dendritic cells trigger vascular leakage through metalloproteinase overproduction.
abstract: 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.
authors.affiliation: Institut de Recherche pour le Développement, IRD, Immunologie Virale et Moléculaire, UR178 IFR122, 34094 Montpellier, France.
authors.forename: Natthanej
authors.initials: N
authors.lastname: Luplertlop
authors.forename: Natthanej
authors.initials: N
authors.lastname: Luplerdlop
authors.forename: Dorothée
authors.initials: D
authors.lastname: Missé
authors.forename: Dorothy
authors.initials: D
authors.lastname: Bray
authors.forename: Virginie
authors.initials: V
authors.lastname: Deleuze
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Gonzalez
authors.forename: Vijittra
authors.initials: V
authors.lastname: Leardkamolkarn
authors.forename: Hans
authors.initials: H
authors.lastname: Yssel
authors.forename: Francisco
authors.initials: F
authors.lastname: Veas
mesh_terms: D002199:Capillary Permeability; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology / Q000821:virology*; D003716:Dengue Virus / Q000276:immunology; D004730:Endothelium, Vascular / Q000276:immunology / Q000821:virology; D006801:Humans; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019595:Severe Dengue / Q000150:complications / Q000276:immunology / Q000378:metabolism*; D013577:Syndrome
chemical_list: D017077:Culture Media, Conditioned; D045726:Metalloproteases