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 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 4

Improvement of vascular leakage in severe DENV infection models.

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Improvement of vascular leakage in severe DENV infection models. AG129 m...
AG129 mice were infected with a low (1 × 106 PFU) or high (5 × 107 PFU) dose of DENV and either mock or nafamostat mesylate treated beginning 1 hour after infection. Uninfected, n = 3; DENV infected, vehicle treated, n = 4–5; and DENV infected, nafamostat mesylate treated, n = 4–5. (A) At 24 hours after infection, hematocrit was measured. A single treatment of nafamostat mesylate reversed DENV-induced vascular leakage for both infection doses. (B and C) Nafamostat mesylate effectively restored hematocrit values to baseline levels at days 2 and 3 after infection in an antibody-enhanced DENV mouse model. Treatment was initiated (B) 1 hour or delayed (C) 24 hours after infection and given at 24-hour intervals thereafter. Statistical significance was calculated using 1-way ANOVA with Bonferroni’s multiple comparison test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. For all panels, data are presented as mean ± SEM.