Oral Presentation Lorne Infection and Immunity 2013

Severe Immunopathology Induced by Influenza A Virus is Due to PB1-F2-Mediated Activation of the NLRP3 Inflammasome (#8)

Ashley Mansell 1 , Michelle Tate 1 , Anita Pinar 1 , Charley MacKenzie-Kludas 2 , Weiguang Zeng 2 , Andrea Stutz 3 , Eicke Latz 3 4 , Lorena Brown 2 , Julie McAuley 2
  1. Monash Institute of Medical Research, Clayton, VIC, Australia
  2. Department of Microbiology and Immunology, University of Melbourne, Melbourne, VIC, Australia
  3. Institute of Innate Immunity, University Hospitals, University of Bonn, Bonn, Germany
  4. Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

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.