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 3

Tryptase inhibition therapeutically blocks vascular leakage during DENV infection.

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Tryptase inhibition therapeutically blocks vascular leakage during DENV ...
Mice (n = 3–5 per group) were either mock infected or infected with DENV (1 × 106 PFU), followed by treatment with vehicle control (saline) or using a specific tryptase inhibitor, nafamostat mesylate, at a dose of 0.06 mg/kg. (A) Hematocrit analysis was performed using an automated hematology analyzer on whole blood at 24 hours after treatment. (B) Serum was isolated to measure tryptase activity by enzymatic assay. Only DENV-infected mice that were vehicle treated had elevated tryptase activity over uninfected control group. Nafamostat mesylate treatment reversed tryptase activity to baseline levels. (C) Platelet counts at 24 hours are presented. The data show a strong reduction in DENV-induced vascular leakage upon treatment with tryptase inhibitor, nafamostat mesylate, but no significant difference in platelet counts compared with DENV-infected and vehicle-treated mice. For A–C, statistical significance was determined using 1-way ANOVA with Bonferroni’s multiple comparison test. (D) No difference in the DENV burden in the spleen determined by real-time reverse-transcription PCR (RT-PCR) was observed between vehicle- and nafamostat mesylate–treated animals at 72 hours after infection by Student’s unpaired t test. For all panels, data are presented as mean ± SEM. *P < 0.05; ****P < 0.0001.