The ability of the host to recognize infection by the innate immune system is critical for virus clearance, initiating a potent proinflammatory response. Recent studies have highlighted the role of the cytosolic multiprotein inflammasome complex in initiating inflammation via maturation of IL-1b. The inflammasome complex recognise a wide range of ‘danger’ signals including bacterial toxins, reactive oxygen species, crystalline material, protein aggregates and endogenous danger signals such as urate crystals.
PB1-F2 expressed by pathogenic influenza A viruses (IAV) contributes to the pathophysiology of infection, although a mechanism is unclear. We investigated PB1-F2 activation of the innate immune response.
We found that PB1-F2 induces secretion of the pyrogenic cytokine IL-1b by activating the NLRP3 inflammasome and contributes to the heightened inflammatory response to infection. Using PB1-F2 peptides derived from pathogenic IAV, we demonstrate enhanced IL-1β secretion and inflammation compared to a non-pathogenic PB1-F2. Furthermore, PB1-F2 peptide induces IL-1β secretion in both human PBMCs and murine macrophages in a Caspase-1- and NLRP3-dependent manner. Critically, NLRP3-deficient mice exhibit decreased inflammation following PB1-F2 challenge in vivo, compared to wild type mice.
To our knowledge, this is the first characterization of the mechanism of PB1-F2-mediated NLRP3 inflammasome complex activation, providing further understanding of PB1-F2 contribution to the enhanced inflammatory phenotype in pathogenic influenza infections. These studies also suggest that viral protein aggregates may act as a novel ‘class’ of pathogen danger signals.