Activation of the NLRP3 Inflammasome by IAV Virulence Protein PB1-F2 Contributes to Severe Pathophysiology and Disease

The ability for a host to recognize infection is critical for virus clearance and often begins with induction of inflammation. the pb1-f2 of pathogenic influenza a viruses (iav) contributes to the pathophysiology of infection,although the mechanism for this is unclear. the nlrp3-inflammasome has been implicated in iav pathogenesis,but whether iav virulence proteins can be activators of the complex is unknown. we investigated whether pb1-f2-mediated activation of the nlrp3-inflammasome is a mechanism contributing to overt inflammatory responses to iav infection. we show pb1-f2 induces secretion of pyrogenic cytokine il-1β by activating the nlrp3-inflammasome,contributing to inflammation triggered by pathogenic iav. compared to infection with wild-type virus,mice infected with reverse engineered pb1-f2-deficient iav resulted in decreased il-1β secretion and cellular recruitment to the airways. moreover,mice exposed to pb1-f2 peptide derived from pathogenic iav had enhanced il-1β secretion compared to mice exposed to peptide derived from seasonal iav. implicating the nlrp3-inflammasome complex specifically,we show pb1-f2 derived from pathogenic iav induced il-1β secretion was caspase-1-dependent in human pbmcs and nlrp3-dependent in mice. importantly,we demonstrate pb1-f2 is incorporated into the phagolysosomal compartment,and upon acidification,induces asc speck formation. we also show that high molecular weight aggregated pb1-f2,rather than soluble pb1-f2,induces il-1β secretion. furthermore,nlrp3-deficient mice exposed to pb1-f2 peptide or infected with pb1-f2 expressing iav were unable to efficiently induce the robust inflammatory response as observed in wild-type mice. in addition to viral pore forming toxins,ion channel proteins and rna,we demonstrate inducers of nlrp3-inflammasome activation may include disordered viral proteins,as exemplified by pb1-f2,acting as host pathogen 'danger' signals. elucidating immunostimulatory pb1-f2 mediation of nlrp3-inflammasome activation is a major step forward in our understanding of the aetiology of disease attributable to exuberant inflammatory responses to iav infection. © 2013 mcauley et al.