Th1-Polarized, Dengue Virus-Activated Human Mast Cells Induce Endothelial Transcriptional Activation and Permeability

Ayesa Syenina,Cyril J Jagaraj,Duane J Gubler,Soman N Abraham,Ashley L St John,Michel Arock,Siham Bibi,Abhay P S Rathore,Wilfried A A Saron

doi:10.3390/v12121379

Abstract

Dengue virus (DENV), an arbovirus, strongly activates mast cells (MCs), which are key immune cells for pathogen immune surveillance. In animal models, MCs promote clearance of local peripheral DENV infections but, conversely, also promote pathological vascular leakage when widely activated during systemic DENV infection. Since DENV is a human pathogen, we sought to ascertain whether a similar phenomenon could occur in humans by characterizing the products released by human MCs (huMCs) upon direct (antibody-independent) DENV exposure, using the phenotypically mature huMC line, ROSA. DENV did not productively infect huMCs but prompted huMC release of proteases and eicosanoids and induced a Th1-polarized transcriptional profile. In co-culture and trans-well systems, huMC products activated human microvascular endothelial cells, involving transcription of vasoactive mediators and increased monolayer permeability. This permeability was blocked by MC-stabilizing drugs, or limited by drugs targeting certain MC products. Thus, MC stabilizers are a viable strategy to limit MC-promoted vascular leakage during DENV infection in humans.

Highlights

Mast cells (MCs) are granulated cells found at the interface between the host and environment, such as in the skin and mucosa [1,2]
We show that dengue virus (DENV)-mediated activation of human MCs (huMCs) is characterized by induction of
We observed that the mast cells (MCs) products that are produced immediately, within 1 h of huMC exposure to DENV, promote significant breakdown of the tight junctions between human microvascular endothelial cell (huMEC), allowing permeability in endothelial monolayers

Summary

Introduction

Mast cells (MCs) are granulated cells found at the interface between the host and environment, such as in the skin and mucosa [1,2]. As key innate immune cells, they are involved in the earliest phase of host defense due to their capacity. Products that MCs secrete during the acute inflammatory response include preformed mediators and de novo synthesized products, such as histamine, MC-specific proteases, eiocosanoids (e.g., leukotrienes and prostaglandins), cytokines and chemokines [2]. Many of these products are known to contribute to endothelial activation, regulate the coagulation cascade, promote vascularization and/or increase vascular permeability [4,5]. A key viral pathogen of interest is dengue virus (DENV), since this arboviral pathogen is injected into the skin (where MCs are highly abundant) by mosquitos. DENV disease is characterized by a febrile illness involving signs of vascular leakage that range from mild to severe clinical manifestations; when mild, referred to as dengue fever (DF) and when severe, termed dengue hemorrhagic fever (DHF) [12]

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