PB1-F2 Peptide Derived from Avian Influenza A Virus H7N9 Induces Inflammation via Activation of the NLRP3 Inflammasome

Abstract

The emergence of avian H7N9 influenza A virus in humans with associated high mortality has highlighted the threat of a potential pandemic. Fatal H7N9 infections are characterized by hyperinflammation and increased cellular infiltrates in the lung. Currently there are limited therapies to address the pathologies associated with H7N9 infection and the virulence factors that contribute to these pathologies. We have found that PB1-F2 derived from H7N9 activates the NLRP3 inflammasome and induces lung inflammation and cellular recruitment that is NLRP3-dependent. We have also shown that H7N9 and A/Puerto Rico/H1N1 (PR8)PB1-F2 peptide treatment induces significant mitochondrial reactive oxygen production, which contributes to NLRP3 activation. Importantly, treatment of cells or mice with the specific NLRP3 inhibitor MCC950 significantly reduces IL-1β maturation, lung cellular recruitment, and cytokine production. Together, these results suggest that PB1-F2 from H7N9 avian influenza A virus may be a major contributory factor to disease pathophysiology and excessive inflammation characteristic of clinical infections and that targeting the NLRP3 inflammasome may be an effective means to reduce the inflammatory burden associated with H7N9 infections.

Membrane vesicles from Pseudomonas aeruginosa activate the noncanonical inflammasome through caspase‐5 in human monocytes

“…To investigate inflammasome activation by P. aeruginosa OMVs, we first used NLRP3‐deficient macrophages stably reconstituted with cerulean‐tagged ASC and NLRP3‐Flag (ASC‐cerulean IMACs), which obviates the need for signal 1 in inflammasome activation . These ASC‐cerulean IMACs can therefore be used to visualize the ability of a given stimulus to promote inflammasome activation, as assessed by ASC “speck” formation (Supplementary movie 1). Live‐cell imaging of these cells showed uptake of OMVs (Supplementary movies 2–6), followed by oligomerization of the ASC molecules into discrete specks at approximately 14 h post‐OMV‐treatment (Figure a; Supplementary movie 1).…”

Regulation and functions of NLRP3 inflammasome during influenza virus infection

“…A role for PB1-F2-mediated NLRP3 inflammasome activation in the pathogenesis of influenza virus infection is also demonstrated in another recent study. PB1-F2 from the recently emerged avian origin H7N9 influenza virus induces NLRP3-dependent IL-1β production, lung inflammation and cellular recruitment (Pinar et al, 2016). Importantly, treatment with NLRP3 inhibitor MCC950 significantly decreases the observed hyper inflammatory responses further suggesting NLRP3 inhibition as an effective treatment option during pathogenic influenza virus infection (Pinar et al, 2016).…”

Die Another Way: Interplay between Influenza A Virus, Inflammation and Cell Death

“…In addition, extracellular adenosine 5 -triphosphate (ATP) released from dead/dying cells activates the P2X purinoceptor 7 (P2X7) receptor, resulting in potassium efflux, as well as reactive oxygen species (ROS) generation, which can activate NLRP3 inflammasome assembly [18][19][20]. Importantly, the IAV PB1-F2 protein from pathogenic H1N1 and H7N9, but not seasonal IAV, can induce mitochondrial ROS production, which also contributes to NLRP3 activation [21,22]. More recently, Z-DNA binding protein-1 (ZBP1), also known as DNA-dependent activator of IFN-regulatory factors (DAI), has been shown to sense viral RNA to trigger NLRP3 inflammasome assembly [23,24].…”