Dengue-virus-infected dendritic cells trigger vascular leakage through metalloproteinase overproduction.
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.
Luplertlop
Natthanej
N
Institut de Recherche pour le Développement, IRD, Immunologie Virale et Moléculaire, UR178 IFR122, 34094 Montpellier, France.
Luplerdlop
Natthanej
N
Missé
Dorothée
D
Bray
Dorothy
D
Deleuze
Virginie
V
Gonzalez
Jean-Paul
JP
Leardkamolkarn
Vijittra
V
Yssel
Hans
H
Veas
Francisco
F
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
D017077:Culture Media, Conditioned; D045726:Metalloproteases