Neutrophil Extracellular Traps in Dengue Are Mainly Generated NOX-Independently.

Fadel Muhammad Garishah,Nils Rother,Ronald P Van Rij,Johan Van Der Vlag,Bachti Alisjahbana,Quirijn De Mast,Gijs J Overheul,André Van Der Ven,Silvita Fitri Riswari

doi:10.3389/fimmu.2021.629167

Abstract

Neutrophil extracellular traps (NETs) are increasingly recognized to play a role in the pathogenesis of viral infections, including dengue. NETs can be formed NADPH oxidase (NOX)-dependently or NOX-independently. NOX-independent NETs can be induced by activated platelets and are very potent in activating the endothelium. Platelet activation with thrombocytopenia and endothelial dysfunction are prominent features of dengue virus infection. We postulated that dengue infection is associated with NOX-independent NET formation, which is related to platelet activation, endothelial perturbation and increased vascular permeability. Using our specific NET assays, we investigated the time course of NET formation in a cohort of Indonesian dengue patients. We found that plasma levels of NETs were profoundly elevated and that these NETs were predominantly NOX-independent NETs. During early recovery phase (7-13 days from fever onset), total NETs correlated negatively with platelet number and positively with platelet P-selectin expression, the binding of von Willebrand factor to platelets and levels of Syndecan-1. Patients with gall bladder wall thickening, an early marker of plasma leakage, had a higher median level of total NETs. Ex vivo, platelets induced NOX-independent NET formation in a dengue virus non-structural protein 1 (NS1)-dependent manner. We conclude that NOX-independent NET formation is enhanced in dengue, which is most likely mediated by NS1 and activated platelets.

Highlights

Dengue is the most important arboviral infection worldwide, occurring in more than 125 countries [1]
nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-dependent Neutrophil extracellular traps (NETs) are characterized by cleavage of the histone N-terminal tails, whereas in NOX-independent NETs, histone N-terminal tails are preserved [27]
Using a NET assay that detect unmodified Nterminal histone tails on NETs [16], we show that NET formation in dengue is predominantly NOX-independent

Summary

Introduction

Dengue is the most important arboviral infection worldwide, occurring in more than 125 countries [1]. The most important complications are a transient vascular permeability syndrome and bleeding [2]. The pathogenesis of these complications is still incompletely understood. Neutrophil extracellular traps (NETs) are web-like chromatin structures released by neutrophils upon exposure to both infectious or non-infectious stimuli. These web-like chromatin structures are decorated with histones and anti-microbial peptides, such as myeloperoxidase (MPO), neutrophil elastase (NE) and cathepsin G (CatG) [3]. The primary function of NETs is to capture, immobilize and kill pathogens within the host They can inadvertently result in endothelial and tissue damage, inflammation and increased vascular permeability [4, 5]

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Conclusion