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PLoS Pathog ; 9(5): e1003392, 2013.
Article in English | MEDLINE | ID: mdl-23737748

ABSTRACT

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-1ß 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-1ß secretion and cellular recruitment to the airways. Moreover, mice exposed to PB1-F2 peptide derived from pathogenic IAV had enhanced IL-1ß 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-1ß 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-1ß 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.


Subject(s)
Carrier Proteins/metabolism , Inflammasomes/metabolism , Influenza A virus/metabolism , Influenza, Human/metabolism , Viral Proteins/immunology , Virulence Factors/metabolism , Animals , Carrier Proteins/genetics , Carrier Proteins/immunology , Cell Line, Transformed , Female , Humans , Inflammasomes/genetics , Inflammasomes/immunology , Inflammation/genetics , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Inflammation/physiopathology , Inflammation/virology , Influenza A virus/genetics , Influenza A virus/immunology , Influenza A virus/pathogenicity , Influenza, Human/genetics , Influenza, Human/immunology , Influenza, Human/physiopathology , Interleukin-1beta/genetics , Interleukin-1beta/immunology , Interleukin-1beta/metabolism , Male , Mice , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein , Viral Proteins/genetics , Viral Proteins/metabolism , Virulence Factors/genetics , Virulence Factors/immunology
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