Abstract
Acute viral bronchiolitis by Respiratory Syncytial Virus (RSV) is the most common respiratory illness in children in the first year of life. RSV bronchiolitis generates large numbers of hospitalizations and an important burden to health systems. Neutrophils and their products are present in the airways of RSV-infected patients who developed increased lung disease. Neutrophil Extracellular Traps (NETs) are formed by the release of granular and nuclear contents of neutrophils in the extracellular space in response to different stimuli and recent studies have proposed a role for NETs in viral infections. In this study, we show that RSV particles and RSV Fusion protein were both capable of inducing NET formation by human neutrophils. Moreover, we analyzed the mechanisms involved in RSV Fusion protein-induced NET formation. RSV F protein was able to induce NET release in a concentration-dependent fashion with both neutrophil elastase and myeloperoxidase expressed on DNA fibers and F protein-induced NETs was dismantled by DNase treatment, confirming that their backbone is chromatin. This viral protein caused the release of extracellular DNA dependent on TLR-4 activation, NADPH Oxidase-derived ROS production and ERK and p38 MAPK phosphorylation. Together, these results demonstrate a coordinated signaling pathway activated by F protein that led to NET production. The massive production of NETs in RSV infection could aggravate the inflammatory symptoms of the infection in young children and babies. We propose that targeting the binding of TLR-4 by F protein could potentially lead to novel therapeutic approaches to help control RSV-induced inflammatory consequences and pathology of viral bronchiolitis.
Highlights
Respiratory Syncytial Virus (RSV)-induced acute bronchiolitis is the most prevalent respiratory disease in children under age 2 years, and its seasonal epidemics are associated with a significant number of hospital admissions, with a huge burden to communities worldwide [1]
It has been previously shown that neutrophils and their products are present in the airways of patients and animals infected with RSV [12,13,14]
Human neutrophils were stimulated with different concentrations of F protein in vitro and after 3 h of incubation extracellular DNA was quantified in culture supernatants
Summary
Respiratory Syncytial Virus (RSV)-induced acute bronchiolitis is the most prevalent respiratory disease in children under age 2 years, and its seasonal epidemics are associated with a significant number of hospital admissions, with a huge burden to communities worldwide [1]. Almost 70% of all children are infected with RSV during the first year of life, and by age 3, practically all children will have experienced at least one infection with this virus [2, 3]. It has been recently shown that RSV F protein directly interacts with the MD-2–TLR-4 complex, activating the transcription factor NF-κB [10]. These studies highlight the importance of specific signaling pathways activated by F protein to stimulate inflammation
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