Abstract
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.
Highlights
Dengue (DENV) is a mosquito-borne flavivirus that causes up to 390 million infections, 96 million cases of dengue, and ~500,000 hospitalizations annually
We previously demonstrated that nonstructural protein 1 (NS1), the only protein secreted from dengue virus (DENV)-infected cells, can both trigger vascular leak in mice when given systemically and increase permeability in human pulmonary endothelial cells via disruption of the endothelial glycocalyxlike layer, the molecular barrier that lines blood vessels
We demonstrated that Dengue virus (DENV) NS1 induces localized vascular leak in the dermis of wild-type mice and that this effect is specific to DENV NS1 and independent of Toll-like receptor 4 (TLR4) and TNF-α signaling
Summary
Dengue (DENV) is a mosquito-borne flavivirus that causes up to 390 million infections, 96 million cases of dengue, and ~500,000 hospitalizations annually. Secreted DENV NS1 circulates in the blood during acute illness, and serum NS1 levels correlate with dengue disease severity, as does viral load (i.e., viremia) [4]. Disruption of the endothelial barrier can result in excessive leak across the endothelium, a phenomenon known as hyperpermeability. This manifests as vascular leakage, where fluid accumulates in tissues after extravasating from the vasculature [5, 6]. Disruption of the glycocalyx has been shown to lead to vascular pathology and has been previously hypothesized to play a role in the pathogenesis of severe dengue disease [10], and modulation of the glycocalyx under inflammatory conditions is thought to contribute to various diseases [11]
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