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Dengue Virus NS1 Disrupts the Endothelial Glycocalyx, Leading to Hyperpermeability.

ABSTRACT: Dengue is the most prevalent arboviral disease in humans and a major public health problem worldwide. Systemic plasma leakage, leading to hypovolemic shock and potentially fatal complications, is a critical determinant of dengue severity. Recently, we and others described a novel pathogenic effect of secreted dengue virus (DENV) non-structural protein 1 (NS1) in triggering hyperpermeability of human endothelial cells in vitro and systemic vascular leakage in vivo. NS1 was shown to activate toll-like receptor 4 signaling in primary human myeloid cells, leading to secretion of pro-inflammatory cytokines and vascular leakage. However, distinct endothelial cell-intrinsic mechanisms of NS1-induced hyperpermeability remained to be defined. The endothelial glycocalyx layer (EGL) is a network of membrane-bound proteoglycans and glycoproteins lining the vascular endothelium that plays a key role in regulating endothelial barrier function. Here, we demonstrate that DENV NS1 disrupts the EGL on human pulmonary microvascular endothelial cells, inducing degradation of sialic acid and shedding of heparan sulfate proteoglycans. This effect is mediated by NS1-induced expression of sialidases and heparanase, respectively. NS1 also activates cathepsin L, a lysosomal cysteine proteinase, in endothelial cells, which activates heparanase via enzymatic cleavage. Specific inhibitors of sialidases, heparanase, and cathepsin L prevent DENV NS1-induced EGL disruption and endothelial hyperpermeability. All of these effects are specific to NS1 from DENV1-4 and are not induced by NS1 from West Nile virus, a related flavivirus. Together, our data suggest an important role for EGL disruption in DENV NS1-mediated endothelial dysfunction during severe dengue disease.

SUBMITTER: Puerta-Guardo H

PROVIDER: S-EPMC4944995 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Dengue Virus NS1 Disrupts the Endothelial Glycocalyx, Leading to Hyperpermeability.

Puerta-Guardo Henry H Glasner Dustin R DR Harris Eva E

PLoS pathogens 20160714 7

Dengue is the most prevalent arboviral disease in humans and a major public health problem worldwide. Systemic plasma leakage, leading to hypovolemic shock and potentially fatal complications, is a critical determinant of dengue severity. Recently, we and others described a novel pathogenic effect of secreted dengue virus (DENV) non-structural protein 1 (NS1) in triggering hyperpermeability of human endothelial cells in vitro and systemic vascular leakage in vivo. NS1 was shown to activate toll- ...[more]

PMID: 27416066

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Project description:Pathological hyperpermeability is a morbidity involved in various systemic diseases, including sepsis. The endothelial glycocalyx layer (GCX) plays a key role in controlling vascular permeability and could be a useful therapeutic target. The purpose of the present study was to analyze the functional role of the GCX in vascular permeability and to elucidate its role in pathological conditions. First, male C57BL/6J wild-type mice were used as in vivo models to study the effects of sepsis and the pharmacological digestion of glycosaminoglycans (GAGs) on the GCX. Vascular permeability was evaluated using fluorescein isothiocyanate (FITC)-labeled dextran. Second, the changes in gene expression in vascular endothelial cells after GAGs digestion were compared between a control and a septic model using RNA sequencing. In the in vivo study, the glycocalyx was depleted in both the septic model and the group with pharmacological GAGs digestion. FITC-labeled dextran had leaked into the interstitium in the septic group, but not in the other groups. In the in vitro study, histamine decreased the transendothelial electrical resistance (TEER), indicating an increase in permeability. GAGs digestion alone did not change the TEER, and the effect of histamine on the TEER was not enhanced by GAGs digestion. The gene expression profiles after GAGs digestion differed from the control condition, indicating the initiation of signal transduction. In conclusion, we demonstrated that the structural barrier of the GCX does not solely determine the fluid permeability of the endothelial layer, since enzymatic depletion of the GCX did not increase the permeability. The gene expression findings suggest that the digestion of GAGs alone did not induce hyperpermeability either in vitro or in vivo, although sepsis did induce hyperpermeability. While GAGs degradation by itself does not appear to induce hyperpermeability, it may play an important role in initiating signal transductions.

Dataset Information

Dengue Virus NS1 Disrupts the Endothelial Glycocalyx, Leading to Hyperpermeability.

Publications

Dengue Virus NS1 Disrupts the Endothelial Glycocalyx, Leading to Hyperpermeability.

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