Th1-polarized, dengue virus-activated human mast cells induce endothelial transcriptional activation and permeability

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

doi:10.3390/v12121379

Th1-polarized, dengue virus-activated human mast cells induce endothelial transcriptional activation and permeability

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	1379
Pages (from-to)	1-15
Number of pages	15
Journal	Viruses
Volume	12
Issue number	12
DOIs	https://doi.org/10.3390/v12121379
Publication status	Published - 2 Dec 2020
Externally published	Yes

Bibliographical note

Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

Chymase
Dengue
Endothelial permeability
Human
Mast cell

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10.3390/v12121379Licence: CC BY

Publisher version (open access)Final published version, 2.47 MBLicence: CC BY

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title = "Th1-polarized, dengue virus-activated human mast cells induce endothelial transcriptional activation and permeability",

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.",

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T1 - Th1-polarized, dengue virus-activated human mast cells induce endothelial transcriptional activation and permeability

AU - Syenina, Ayesa

AU - Saron, Wilfried A. A.

AU - Jagaraj, Cyril J.

AU - Bibi, Siham

AU - Arock, Michel

AU - Gubler, Duane J.

AU - Rathore, Abhay P. S.

AU - Abraham, Soman N.

AU - St. John, Ashley L.

N1 - Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2020/12/2

Y1 - 2020/12/2

N2 - 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.

AB - 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.

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Th1-polarized, dengue virus-activated human mast cells induce endothelial transcriptional activation and permeability

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