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 2

MC proteases promote vascular leakage and shock in vivo.

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MC proteases promote vascular leakage and shock in vivo. (A) Hematocrit ...
(A) Hematocrit values were obtained 6 hours after injection with saline alone or 30 ng of either tryptase, chymase, or OVA. Means differ significantly by 1-way ANOVA (P < 0.0001). Bonferroni’s multiple comparison test was used to determine significance among groups. Control, n = 15; tryptase and chymase, n = 10; OVA, n = 5. Data were added from 2 independent experiments. (B and C) Mice (n = 3–4) were injected with 30 ng each of tryptase, chymase, or OVA i.v., or an equivalent volume of saline was injected for controls. To measure shock, the body temperature of animals was recorded every 5 minutes for the first 15 minutes and subsequently at 10-minute intervals. (B) Both tryptase and chymase caused sudden drops in body temperature, indicative of shock, compared with both OVA and saline control groups. Data were analyzed by 2-way ANOVA with Holm-Šidák multiple comparison test to compare temperatures at each time point. (C) The maximal difference in temperature during the time course is presented, suggesting that tryptase treatment causes significantly higher plasma loss in animals compared with chymase, OVA, and saline control groups, determined by 1-way ANOVA with Holm-Šidák multiple comparison test. Data are shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.