NEW YORK (Reuters Health) – Dengue virus causes vascular leak through its nonstructural protein 1 (NS1)-mediated disruption of endothelial glycocalyx components, researchers report.
“We think the results from our study are particularly interesting because they further validate a role for NS1 as a driver of pathogenesis in vivo,” Dr. Eva Harris from University of California, Berkeley, told Reuters Health by email. “Of particular note are the results both in vitro and in vivo that inhibitors of sialidase, cathepsin L, and heparanase are sufficient to protect from NS1-induced leak and endothelial dysfunction via the endothelial cell-intrinsic mechanism.”
Severe dengue virus disease causes vascular leakage, which can lead to shock and death. Dr. Harris’s team previously demonstrated that NS1, the only protein secreted from dengue virus-infected cells, triggers vascular leak in mice when given systemically and increases permeability in human pulmonary endothelial cells by disrupting the endothelial glycocalyx-like layer, the molecular barrier that outlines blood vessels.
NS1 also triggers release of inflammatory cytokines, so Dr. Harris and colleagues, in the current study, explored the relative contributions of inflammatory molecules and the endothelial glycocalyx-like layer to NS1-mediated pathogenesis.
In an in vitro model of endothelial permeability, NS1 triggered hyperpermeability independently of the pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin-6.
Similarly, in vivo, NS1 induced localized vascular leakage in the dermis of mice independently of TNF-alpha and Toll-like receptor 4 (TLR4) signaling, according to the November 9 PLoS Pathogens online report.
Inhibition of sialidase, cathepsin, and heparanase – enzymes responsible for degrading the endothelial glycocalyx layer and whose expression and activation are triggered by NS1 – prevented NS1-induced vascular leakage.
“Taken together, our results indicate that dengue virus NS1 acts directly on the endothelium to induce vascular leak in vivo that is dependent on components of the glycocalyx,” the researchers conclude.
“In terms of therapeutics, our results raise interesting questions about inhibition of specific enzymes activated in the endothelium, particularly sialidases,” Dr. Harris said. “There are already sialidase inhibitors on the market for influenza that may be potentially useful in severe dengue. Regardless, these endothelial-intrinsic mechanisms are a piece of a larger puzzle, whereby multiple mechanisms synergize, leading to vascular leak.”
“Clinically, our results support observations made in patients with dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) where higher levels of certain glycocalyx components can be found in circulation, as compared to less severe forms of dengue, suggesting potential diagnostic or prognostic markers for severe dengue disease,” she said.
“Ultimately, though our work has implications for treatment and potential early diagnosis of severe dengue disease, there remains a gap between our findings and immediate clinical relevance,” Dr. Harris explained. “However, our observations regarding the glycocalyx raise interesting points about clinical management of severe dengue, specifically in relation to the use of dextran as a colloid during fluid management – a treatment that has been hypothesized to replace components of the glycocalyx during endothelial barrier dysfunction and thus contribute to stabilizing the endothelium.”
She added, “We have only recently begun to understand the complex role that NS1 plays in dengue pathogenesis, and although we have identified a role for the endothelial glycocalyx in NS1-induced vascular leak, the complete picture is undoubtedly more complex, especially in the presence of virus. It is important to continue investigating the mechanisms driving NS1-related pathogenesis and the factors contributing to vascular leak during severe dengue disease.”
SOURCE: http://bit.ly/2hzcjWX
PLoS Pathogens 2017.
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