Dengue virus non-structural protein 1 activates the p38 MAPK pathway to decrease barrier integrity in primary human endothelial cells

The Journal of General Virology
Arturo Barbachano-GuerreroChristine A King

Abstract

Dengue virus (DENV) causes an estimated 390 million infections worldwide annually, with severe forms of disease marked by vascular leakage. Endothelial cells (EC) are directly responsible for vascular homeostasis and are highly responsive to circulating mediators but are not commonly infected. DENV encodes seven non-structural (NS) proteins; with only one of those, NS1, secreted from infected cells and accumulating in the blood of patients. NS1 has been implicated in the pathogenesis of vascular permeability, but the mechanism is not completely understood. Here we used primary endothelial cells and an array of in vitro approaches to study the effect of NS1 in disease-relevant human ECs. Confocal microscopy demonstrated rapid NS1 internalization by ECs into endosomes with accumulation over time. Transcriptomic and pathway analysis showed significant changes in functions associated with EC homeostasis and vascular permeability. Functional significance of this activation was assessed by trans-endothelial electrical resistance and showed that NS1 induced rapid and transient loss in EC barrier function within 3 h post-treatment. To understand the molecular mechanism by which NS1 induced EC activation, we evaluated the stress-sensing...Continue Reading

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Citations

Feb 11, 2021·International Journal of Molecular Sciences·Sarah Seeherman, Yuichiro J Suzuki
Aug 11, 2021·Viruses·Thanyaporn DechtawewatSansanee Noisakran

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