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      Flavivirus NS1 Triggers Tissue-Specific Vascular Endothelial Dysfunction Reflecting Disease Tropism

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          SUMMARY

          Flaviviruses cause systemic or neurotropic-encephalitic pathology in humans. The flavivirus nonstructural protein 1 (NS1) is a secreted glycoprotein involved in viral replication, immune evasion, and vascular leakage during dengue virus infection. However, the contribution of secreted NS1 from related flaviviruses to viral pathogenesis remains unknown. Here, we demonstrate that NS1 from dengue, Zika, West Nile, Japanese encephalitis, and yellow fever viruses selectively binds to and alters permeability of human endothelial cells from lung, dermis, umbilical vein, brain, and liver in vitro and causes tissue-specific vascular leakage in mice, reflecting the pathophysiology of each flavivirus. Mechanistically, each flavivirus NS1 leads to differential disruption of endothelial glycocalyx components, resulting in endothelial hyperpermeability. Our findings reveal the capacity of a secreted viral protein to modulate endothelial barrier function in a tissue-specific manner both in vitro and in vivo, potentially influencing virus dissemination and pathogenesis and providing targets for antiviral therapies and vaccine development.

          In Brief

          Puerta-Guardo et al. discover that five flavivirus NS1 proteins trigger hyperpermeability and vascular dysfunction in human endothelial cells and mice in a manner reflecting disease tropism. This tissue-specific tropism is partially determined by the capacity of NS1 to bind endothelial cells and is characterized by disruption of endothelial glycocalyx components.

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          Most cited references38

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          The endothelial glycocalyx: composition, functions, and visualization

          This review aims at presenting state-of-the-art knowledge on the composition and functions of the endothelial glycocalyx. The endothelial glycocalyx is a network of membrane-bound proteoglycans and glycoproteins, covering the endothelium luminally. Both endothelium- and plasma-derived soluble molecules integrate into this mesh. Over the past decade, insight has been gained into the role of the glycocalyx in vascular physiology and pathology, including mechanotransduction, hemostasis, signaling, and blood cell–vessel wall interactions. The contribution of the glycocalyx to diabetes, ischemia/reperfusion, and atherosclerosis is also reviewed. Experimental data from the micro- and macrocirculation alludes at a vasculoprotective role for the glycocalyx. Assessing this possible role of the endothelial glycocalyx requires reliable visualization of this delicate layer, which is a great challenge. An overview is given of the various ways in which the endothelial glycocalyx has been visualized up to now, including first data from two-photon microscopic imaging.
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            The structure and function of the endothelial glycocalyx layer.

            Over the past decade, since it was first observed in vivo, there has been an explosion in interest in the thin (approximately 500 nm), gel-like endothelial glycocalyx layer (EGL) that coats the luminal surface of blood vessels. In this review, we examine the mechanical and biochemical properties of the EGL and the latest studies on the interactions of this layer with red and white blood cells. This includes its deformation owing to fluid shear stress, its penetration by leukocyte microvilli, and its restorative response after the passage of a white cell in a tightly fitting capillary. We also examine recently discovered functions of the EGL in modulating the oncotic forces that regulate the exchange of water in microvessels and the role of the EGL in transducing fluid shear stress into the intracellular cytoskeleton of endothelial cells, in the initiation of intracellular signaling, and in the inflammatory response.
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              Endothelial cell-cell junctions: happy together.

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                Author and article information

                Journal
                101573691
                39703
                Cell Rep
                Cell Rep
                Cell reports
                2211-1247
                12 December 2019
                05 February 2019
                27 December 2019
                : 26
                : 6
                : 1598-1613.e8
                Affiliations
                [1 ]Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
                [2 ]These authors contributed equally
                [3 ]Lead Contact
                Author notes

                AUTHOR CONTRIBUTIONS

                H.P.-G., D.R.G., D.A.E., S.B.B., C.W., P.R.B., and E.H. conceived and designed the experiments. H.P.-G., D.R.G., D.A.E., S.B.B., M.P., C.W., and K.R., performed the experiments. H.P.-G., D.R.G., S.B.B., and C.W. performed data analyses. E.H. provided funding, reagents, materials and analysis tools. H.P.-G., D.R.G., D.A.E., S.B.B., and E.H. contributed to writing this paper.

                [* ]Correspondence: eharris@ 123456berkeley.edu
                Article
                NIHMS1546463
                10.1016/j.celrep.2019.01.036
                6934102
                30726741
                d349f291-8da8-4c8d-ba8c-3cde41e3267e

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

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                Cell biology
                Cell biology

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