Dengue virus–elicited tryptase induces endothelial permeability and shock
Abhay P.S. Rathore, … , Duane J. Gubler, Ashley L. St. John
Abhay P.S. Rathore, … , Duane J. Gubler, Ashley L. St. John
Published October 1, 2019; First published July 2, 2019
Citation Information: J Clin Invest. 2019;129(10):4180-4193. https://doi.org/10.1172/JCI128426.
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Research Article Infectious disease Vascular biology

Dengue virus–elicited tryptase induces endothelial permeability and shock

Abstract

Dengue virus (DENV) infection causes a characteristic pathology in humans involving dysregulation of the vascular system. In some patients with dengue hemorrhagic fever (DHF), vascular pathology can become severe, resulting in extensive microvascular permeability and plasma leakage into tissues and organs. Mast cells (MCs), which line blood vessels and regulate vascular function, are able to detect DENV in vivo and promote vascular leakage. Here, we showed that an MC-derived protease, tryptase, is consequential for promoting vascular permeability during DENV infection through inducing breakdown of endothelial cell tight junctions. Injected tryptase alone was sufficient to induce plasma loss from the circulation and hypovolemic shock in animals. A potent tryptase inhibitor, nafamostat mesylate, blocked DENV-induced vascular leakage in vivo. Importantly, in 2 independent human dengue cohorts, tryptase levels correlated with the grade of DHF severity. This study defines an immune mechanism by which DENV can induce vascular pathology and shock.

Authors

Abhay P.S. Rathore, Chinmay Kumar Mantri, Siti A.B. Aman, Ayesa Syenina, Justin Ooi, Cyril J. Jagaraj, Chi Ching Goh, Hasitha Tissera, Annelies Wilder-Smith, Lai Guan Ng, Duane J. Gubler, Ashley L. St. John

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Figure 5

Visualization of inhibition of plasma leakage in DENV-infected mice.

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Visualization of inhibition of plasma leakage in DENV-infected mice. AG1...
AG129 mice were infected with 1 × 106 PFU of DENV i.p. and either treated with nafamostat mesylate or with vehicle. Mice (n = 3), 24 hours after infection, were injected with 70 kDa FITC-dextran. Two-photon images were acquired continuously at 2-second intervals, beginning 5 minutes after injection, for 18 minutes total. (A) Representative images from the indicated time points after FITC-dextran injection from Supplemental Videos 1–3, showing vascular leakage in the DENV-infected mock-treated ear, while control mice and DENV-infected mice treated with nafamostat mesylate showed no visually discernible vascular leakage. Scale bars: 50 μm (B) MFI in the acquired images over time is presented. Intensity was measured by averaging 10 areas in the interstitial space. Data are representative of 3 independent experiments.