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2015 ; 10
(4
): e0124082
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Respiratory syncytial virus fusion protein promotes TLR-4-dependent neutrophil
extracellular trap formation by human neutrophils
#MMPMID25856628
Funchal GA
; Jaeger N
; Czepielewski RS
; Machado MS
; Muraro SP
; Stein RT
; Bonorino CB
; Porto BN
PLoS One
2015[]; 10
(4
): e0124082
PMID25856628
show ga
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.
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