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Th1-Polarized, Dengue Virus-Activated Human Mast Cells Induce Endothelial Transcriptional Activation and Permeability
Ayesa Syenina1, Wilfried A A Saron1, Cyril J Jagaraj1
1Program in Emerging Infectious Diseases, Duke-National University of Singapore, Singapore 169857, Singapore.
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.
Insights
Dengue virus (DENV) activates human mast cells (huMCs), which release products causing vascular leakage. MC stabilizers can prevent this DENV-induced vascular leakage in humans.
Area of Science:
- Immunology
- Virology
- Pathology
Background:
- Mast cells (MCs) are crucial for immune surveillance and can promote or hinder dengue virus (DENV) infection outcomes.
- Animal models show MCs aid local DENV clearance but cause vascular leakage in systemic infections.
Purpose of the Study:
- To investigate if human mast cells (huMCs) exhibit similar DENV-induced vascular leakage.
- To characterize products released by huMCs upon direct DENV exposure.
Main Methods:
- Used the mature huMC line, ROSA, for antibody-independent DENV exposure.
- Analyzed huMC-released proteases and eicosanoids.
- Co-cultured huMCs with human microvascular endothelial cells (huMECs).
- Assessed huMEC activation, mediator transcription, and monolayer permeability.
Main Results:
- DENV did not productively infect huMCs but induced release of proteases and eicosanoids.
- HuMCs exhibited a Th1-polarized transcriptional profile upon DENV exposure.
- HuMC products activated huMECs, increasing vascular permeability.
- MC-stabilizing drugs or drugs targeting MC products blocked this permeability.
Conclusions:
- Human mast cells release mediators that increase vascular permeability during DENV infection.
- MC-stabilizing drugs represent a potential therapeutic strategy against DENV-induced vascular leakage in humans.
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