A pinboard by
Michelle Tate

Post-doctoral scientist, Hudson Institute of Medical Research


Hero turned villain: the role of inflammasomes during influenza virus infections

Severe influenza virus infections, such as those involving 'bird flu' are associated with an over reaction of the immune system which can cause fatal tissue damage. The hosts immune system utilises a protein called an inflammasome, which detects influenza virus infection resulting in promotion of inflammation. We have discovered using small molecule inhibitors, that inflammasomes are protective to the host in the initial phase (0-48 hours) of severe influenza virus infection. However, during the later stages we found inflammasomes contribute to disease by promoting hyperinflammation. Our studies suggest that targeting the inflammasome may be a viable therapeutic option for patients who present to hospital with severe influenza virus infections.

Furthermore, we have discovered a protein expressed by severe influenza viruses called PB1-F2, which can directly activate inflammasomes. Importantly, PB1-F2 protein from influenza viruses which cause mild disease did not activate the inflammasome. Our studies suggest that PB1-F2 protein expressed by severe and fatal influenza viruses may 'over activate' host inflammasomes leading to hyperinflammation.


Activation of the NLRP3 inflammasome by IAV virulence protein PB1-F2 contributes to severe pathophysiology and disease.

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-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.

Pub.: 06 Jun '13, Pinned: 24 Aug '17