Oral Presentation 8th Australasian Virology Society Meeting and 11th Annual Meeting of the Australian Centre for Hepatitis & HIV Virology Meeting 2015

Targeting the NLRP3 inflammasome is a viable option for the treatment of pathogenic influenza virus infections (#3)

Michelle D Tate 1 , Anita Pinar 1 , Jennifer K Dowling 1 , Julie L McAuley 2 , Lorena E Brown 2 , Avril B Robertson 3 , Matt A Cooper 3 , Ashley Mansell 1
  1. Hudson Institute of Medical Research, Clayton, VIC, Australia
  2. Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia
  3. Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia

Fatal influenza A virus (IAV) infections in humans, such as those resulting from spill over of virus from birds, are associated with excessive production of pro-inflammatory cytokines and chemokines. The emergence of novel avian H7N9 IAV in humans with over 700 confirmed cases (38% mortality) and associated hypercytokinemia have highlighted the need to identify the molecular mechanisms that drive these excessive immune responses. Identifying new therapeutic interventions to offset the ineffectiveness of current strategies is paramount to reducing mortality.

We investigated the role of the NLRP3 inflammasome in modulating disease during IAV infection of mice. Using the NLRP3 inhibitor MCC950, we reveal for the first time that NLRP3 plays a biphasic role in modulating IAV disease. Early intranasal MCC950 treatment rendered mice more susceptible to IAV infection; however, late inhibition of NLRP3 reduced local and systemic inflammation and protected against severe disease. Our study defines the role of the NLRP3 inflammasome during pathogenic IAV challenge as both protective and detrimental.

In addition, we demonstrate that the H7N9 IAV protein PB1-F2 activates the NLRP3 inflammasome. Inhibition of phagocytosis, lysosomal acidification and caspase-1 activation or gene deletion of inflammasome components reduced IL-1β secretion by macrophages. Intranasal treatment of mice with H7N9 PB1-F2 peptide induced leukocyte infiltration and IL-1β secretion into the lung airspaces. Our data identifies H7N9 PB1-F2 as a novel inflammasome activator.

NLRP3 activation therefore may initially evoke a protective environment; however protracted activation by pathogenic IAV expressing virulence factors such as PB1-F2 induces damaging inflammasome-mediated inflammation. Our findings significantly advance our immunological understanding of the role of the NLRP3 inflammasome during infectious disease. In addition, these data provide the first evidence that temporally therapeutically targeting the NLRP3 inflammasome may be a clinical option for reducing inflammation associated with pandemic IAV infections such as avian H7N9 and H5N1.