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A Critical Role for Perivascular Cells in Amplifying Vascular Leakage Induced by Dengue Virus Non-Structural Protein 1

Cheung, Yin P., Mastrullo, Valeria, Maselli, Davide, Butsabong, Teemapron, Madeddu, Paolo, Maringer, Kevin and Campagnolo, Paola (2020) A Critical Role for Perivascular Cells in Amplifying Vascular Leakage Induced by Dengue Virus Non-Structural Protein 1 mSphere.

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Abstract

Dengue is the most prevalent arthropod-borne viral disease affecting humans, with severe dengue typified by potentially fatal microvascular leakage and hypovolaemic shock. Blood vessels of the microvasculature are composed of a tubular structure of endothelial cells ensheathed by perivascular cells (pericytes). Pericytes support endothelial cell barrier formation and maintenance through paracrine and contact-mediated signalling, and are critical to microvascular integrity. Pericyte dysfunction has been linked to vascular leakage in noncommunicable pathologies such as diabetic retinopathy, but has never been linked to infection-related vascular leakage. Dengue vascular leakage has been shown to result in part from the direct action of the secreted dengue virus (DENV) non-structural protein NS1 on endothelial cells. Using primary human vascular cells, we show here that NS1 also causes pericyte dysfunction, and that NS1-induced endothelial hyperpermeability is more pronounced in the presence of pericytes. Notably, NS1 specifically disrupted the ability of pericytes to support endothelial cell function in a 3D microvascular assay, with no effect on pericyte viability or physiology. These effects are mediated at least in part through contact-independent paracrine signals involved in endothelial barrier maintenance by pericytes. We therefore identify a role for pericytes in amplifying NS1-induced microvascular hyperpermeability in severe dengue, and thus show that pericytes can play a critical role in the aetiology of an infectious vascular leakage syndrome. These findings open new avenues of research for the development of drugs and diagnostic assays for combating infection-induced vascular leakage, such as severe dengue.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
NameEmailORCID
Cheung, Yin P.
Mastrullo, Valeriav.mastrullo@surrey.ac.uk
Maselli, Davided.maselli@surrey.ac.uk
Butsabong, Teemapron
Madeddu, Paolo
Maringer, Kevink.maringer@surrey.ac.uk
Campagnolo, Paolap.campagnolo@surrey.ac.uk
Date : 25 July 2020
Funders : Medical Research Council, University of Surrey Doctoral College and Department of Chemical and Process Engineering studentship, National Centre for the Replacement, Refinement & Reduction of Animals in Research
Grant Title : Medical Research Council
Uncontrolled Keywords : dengue, haemorrhage, perivascular cell, pericyte, NS1
Additional Information : Embargo OK Metadata Pending
Depositing User : James Marshall
Date Deposited : 29 Jul 2020 09:26
Last Modified : 29 Jul 2020 09:26
URI: http://epubs.surrey.ac.uk/id/eprint/858317

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