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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 identified that a 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 two 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.

SUBMITTER: Rathore AP

PROVIDER: S-EPMC6763290 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Dengue virus-elicited tryptase induces endothelial permeability and shock.

Rathore Abhay Ps AP Mantri Chinmay Kumar CK Aman Siti Ab SA Syenina Ayesa A Ooi Justin J Jagaraj Cyril J CJ Goh Chi Ching CC Tissera Hasitha H Wilder-Smith Annelies A Ng Lai Guan LG Gubler Duane J DJ St John Ashley L AL

The Journal of clinical investigation 20190702 10

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 identified that a MC-derived protease, tryptas ...[more]

PMID: 31265436

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Project description:We studied patients from the Protocolized Care in Early Septic Shock (ProCESS) trial to determine the effects of alternative resuscitation strategies on circulating markers of endothelial cell permeability and hemostasis and the association between biomarkers and mortality.This was a prospective study of biomarkers of endothelial cell permeability (vascular endothelial growth factor [VEGF], soluble fms-like tyrosine kinase 1 [sFLT-1], angiopoietin 2 [Ang-2]) and biomarkers of hemostasis (von Willebrand factor [vWF], thrombomodulin [TM], tissue plasminogen activator [tPA] in 605 of the 1,341 ProCESS participants in a derivation cohort and 305 participants in a validation cohort. Analyses assessed (1) the impact of varying resuscitation strategies on biomarker profiles and (2) the association of endothelial biomarkers with 60-day in-hospital mortality. The study was conducted in 31 US EDs in adult patients with septic shock. Patients were randomly assigned to one of three resuscitation strategies. Blood samples were collected at enrollment, at 6 h, and at 24 h.There were 116 (19.2%) and 52 (17.0%) deaths in the derivation and validation cohorts, respectively. There was no significant association between treatment strategy and any biomarker levels. Permeability (Ang-2 and sFLT-1) and hemostasis (vWF, TM, tPA) biomarkers were higher and VEGF levels were lower in nonsurvivors (P < .05 for all). At baseline, sFLT-1 had the highest point estimate for mortality discrimination (derivation area under the curve [AUC], 0.74; validation, 0.70), similar to lactate (AUC, 0.74) and Sequential Organ Failure Assessment score (AUC, 0.73). In an analysis including all time points and adjusted for age, presence of cancer, and Charlson comorbidity score, the adjusted AUC for sFLT-1 was 0.80.We found no relationship between different resuscitation strategies and biomarker profiles in sepsis, but we did find that elevated levels of endothelial cell biomarkers of permeability and hemostasis were associated with increased mortality.ClinicalTrials.gov; No.: NCT00510835 and NCT00793442; URL: www.clinicaltrials.gov.

Project description:Viruses rely on host cellular metabolism to provide the energy and biosynthetic building blocks required for their replication. Dengue virus (DENV), a member of the Flaviviridae family, is one of the most important arthropod-borne human pathogens worldwide. We analyzed global intracellular metabolic changes associated with DENV infection of primary human cells. Our metabolic profiling data suggested that central carbon metabolism, particularly glycolysis, is strikingly altered during a time course of DENV infection. Glucose consumption is increased during DENV infection and depriving DENV-infected cells of exogenous glucose had a pronounced impact on viral replication. Furthermore, the expression of both glucose transporter 1 and hexokinase 2, the first enzyme of glycolysis, is upregulated in DENV-infected cells. Pharmacologically inhibiting the glycolytic pathway dramatically reduced DENV RNA synthesis and infectious virion production, revealing a requirement for glycolysis during DENV infection. Thus, these experiments suggest that DENV induces the glycolytic pathway to support efficient viral replication. This study raises the possibility that metabolic inhibitors, such as those that target glycolysis, could be used to treat DENV infection in the future.Approximately 400 million people are infected with dengue virus (DENV) annually, and more than one-third of the global population is at risk of infection. As there are currently no effective vaccines or specific antiviral therapies for DENV, we investigated the impact DENV has on the host cellular metabolome to identify metabolic pathways that are critical for the virus life cycle. We report an essential role for glycolysis during DENV infection. DENV activates the glycolytic pathway, and inhibition of glycolysis significantly blocks infectious DENV production. This study provides further evidence that viral metabolomic analyses can lead to the discovery of novel therapeutic targets to block the replication of medically important human pathogens.

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Dengue virus-elicited tryptase induces endothelial permeability and shock.

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Dengue virus-elicited tryptase induces endothelial permeability and shock.

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