Dengue virus NS1 cytokine-independent vascular leak is dependent on endothelial glycocalyx components

Dengue virus (denv) is the most prevalent,medically important mosquito-borne virus. disease ranges from uncomplicated dengue to life-threatening disease,characterized by endothelial dysfunction and vascular leakage. previously,we demonstrated that denv nonstructural protein 1 (ns1) induces endothelial hyperpermeability in a systemic mouse model and human pulmonary endothelial cells,where ns1 disrupts the endothelial glycocalyx-like layer. ns1 also triggers release of inflammatory cytokines from pbmcs via tlr4. here,we examined the relative contributions of inflammatory mediators and endothelial cell-intrinsic pathways. in vivo,we demonstrated that denv ns1 but not the closely-related west nile virus ns1 triggers localized vascular leak in the dorsal dermis of wild-type c57bl/6 mice. in vitro,we showed that human dermal endothelial cells exposed to denv ns1 do not produce inflammatory cytokines (tnf-α,il-6,il-8) and that blocking these cytokines does not affect denv ns1-induced endothelial hyperpermeability. further,we demonstrated that denv ns1 induces vascular leak in tlr4- or tnf-α receptor-deficient mice at similar levels to wild-type animals. finally,we blocked denv ns1-induced vascular leak in vivo using inhibitors targeting molecules involved in glycocalyx disruption. taken together,these data indicate that denv ns1-induced endothelial cell-intrinsic vascular leak is independent of inflammatory cytokines but dependent on endothelial glycocalyx components. © 2017 glasner et al.