PB1-F2 from H7N9 Influenza A virus activates the NLRP3 inflammasome to induce inflammation — ASN Events
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  2. Concurrent Symposia 9 Pattern recognition receptors and responses to pathogens
  3. PB1-F2 from H7N9 Influenza A virus activates the NLRP3 inflammasome to induce inflammation

PB1-F2 from H7N9 Influenza A virus activates the NLRP3 inflammasome to induce inflammation (#296)

Anita Pinar 1 , Michelle Tate 1 , Julie McAuley 2 , Jen Dowling 1 , Eicke Latz 3 4 , Lori Brown 2 , Avril Robertson 5 , Matthew Cooper 5 , Ashley Mansell 1
  1. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
  2. Department of Microbiology and Immunology, University of Melbourne, Melbourne, VIC, Australia
  3. Institute of Innate Immunity, University of Bonn, Bonn, Germany
  4. Division of Infectious Diseases & Immunology, University of Massachusetts Medical School, Worcester, MA, USA
  5. Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia

Emerging influenza A virus (IAV) strains that cross over into humans present a global health danger due to their potential high mortality. These pandemic infections are characterized by the hyper-inflammatory response, or ‘cytokine storm’ which can lead to severe clinical symptoms and death.

We recently identified the virulence factor PB1-F2 in the highly pathogenic mouse-adapted A/PR8 IAV strain as a potent activator of the NLRP3 inflammasome, inducing secretion of mature pyrogenic IL-1b. Activation of the inflammasome was directly linked to pathogenic IAV aetiology. We have now identified that PB1-F2 peptides derived from highly pathogenic strains of the 20th century are also able to induce IL-1b secretion.

Recent sporadic infections of humans in China with avian H7N9 IAV have caused concern due to high mortality, yet virulence factors associated with severe pathology are unclear. H7N9 viruses isolated from human express full length PB1-F2 which may act as a virulence factor. We have found that PB1-F2 peptide derived from H7N9 is a potent inducer of IL-1b secretion, comparable to A/PR8. Importantly, IL-1b secretion is reduced by inhibiting phagocytosis, lysosomal acidification and Caspase-1 activation while macrophages deficient in ASC, Caspase-1 and NLRP3 display ablated IL-1b secretion. Our data therefore identify H7N9 PB1-F2 as a novel inflammasome activator.  Critically treatment of mice with H7N9 PB1-F2 peptide induced leukocyte infiltration and IL-1b secretion into the lung airspaces.

Given the high mortality associated with pathogenic IAV outbreaks, we further investigated if suppression of the inflammasome with the inhibitor MCC950 could reduce inflammation. We have subsequently found that MCC950 is able to potently inhibit PB1-F2-induced IL-1b secretion and inflammasome activation. Importantly within the context of pathogenic IAV outbreaks, treatment of mice with MMC950 three days post-intranasal infection with pathogenic PR8 IAV delays the onset of disease.

These findings suggest that H7N9 IAV pathogenicity may be associated with PB1-F2-induced inflammasome activation and that targeted inhibition of the inflammasome may provide a therapeutic intervention to alleviate the excessive inflammation associated with pathogenic IAV infections.