Abstract
Human respiratory syncytial virus (RSV) constitute highly pathogenic virus that cause severe respiratory diseases in newborn, children, elderly and immuno-compromised individuals. Airway inflammation is a critical regulator of disease outcome in RSV infected hosts. Although “controlled” inflammation is required for virus clearance, aberrant and exaggerated inflammation during RSV infection results in development of inflammatory diseases like pneumonia and bronchiolitis. Interleukin-1β (IL-1β) plays an important role in inflammation by orchestrating the pro-inflammatory response. IL-1β is synthesized as an immature pro-IL-1β form. It is cleaved by activated caspase-1 to yield mature IL-1β that is secreted extracellularly. Activation of caspase-1 is mediated by a multi-protein complex known as the inflammasome. Although RSV infection results in IL-1β release, the mechanism is unknown. Here in, we have characterized the mechanism of IL-1β secretion following RSV infection. Our study revealed that NLRP3/ASC inflammasome activation is crucial for IL-1β production during RSV infection. Further studies illustrated that prior to inflammasome formation; the “first signal” constitutes activation of toll-like receptor-2 (TLR2)/MyD88/NF-κB pathway. TLR2/MyD88/NF-κB signaling is required for pro-IL-1β and NLRP3 gene expression during RSV infection. Following expression of these genes, two “second signals” are essential for triggering inflammasome activation. Intracellular reactive oxygen species (ROS) and potassium (K+) efflux due to stimulation of ATP-sensitive ion channel promote inflammasome activation following RSV infection. Thus, our studies have underscored the requirement of TLR2/MyD88/NF-κB pathway (first signal) and ROS/potassium efflux (second signal) for NLRP3/ASC inflammasome formation, leading to caspase-1 activation and subsequent IL-1β release during RSV infection.
Highlights
Human respiratory syncytial virus (RSV) is a RNA respiratory virus that infects lung epithelial cells to cause high mortality and morbidity among infants, children and elderly by developing severe respiratory diseases like pneumonia and bronchiolitis [1,2,3]
Infection The role of caspase-1 in IL-1b secretion during RSV infection was examined by over-expressing pro-caspase-1 in 293 cells (obtained from American Type Culture Collection (ATCC), Manassas, VA) that endogenously express low levels of procaspase-1. 293 cells were transfected with pro-IL-1b, pro-caspase1 or pcDNA plasmids
Caspase-1 was required for IL-1b production during RSV infection, since higher levels of secreted IL-1b was detected in pro-caspase-1 expressing cells compared to control cells (Fig. 1A)
Summary
Human respiratory syncytial virus (RSV) is a RNA respiratory virus that infects lung epithelial cells to cause high mortality and morbidity among infants, children and elderly by developing severe respiratory diseases like pneumonia and bronchiolitis [1,2,3]. These diseases occur due to massive and ‘‘uncontrolled’’ inflammation of the respiratory tract. The inflammatory response constitutes a critical innate defense mechanism triggered by the host to control infections [7]. Aberrant and unregulated inflammation results in development of various disease states including pneumonia and bronchiolitis
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