Reassessing the role of the NLRP3 inflammasome during pathogenic influenza A virus infection via temporal inhibition

• Published in: Scientific reports 2016-06, Vol.6 (1), p.27912-27912, Article 27912
• Main Authors: Tate, Michelle D., Ong, James D. H., Dowling, Jennifer K., McAuley, Julie L., Robertson, Avril B., Latz, Eicke, Drummond, Grant R., Cooper, Matthew A., Hertzog, Paul J., Mansell, Ashley
• Format: Article
• Language: English
• Subjects: 13/21; 13/31; 631/250/255/1578; 631/250/262/2106/2517; Animals; Avian flu; Bronchoalveolar Lavage Fluid - chemistry; Bronchoalveolar Lavage Fluid - cytology; Cytokine storm; Cytokines - analysis; Drug resistance; Enzyme-Linked Immunosorbent Assay; Humanities and Social Sciences; Immunology; Infections; Infectious diseases; Inflammasomes - antagonists & inhibitors; Inflammasomes - metabolism; Inflammation - prevention & control; Influenza A Virus, H3N2 Subtype - pathogenicity; Leukocytes - cytology; Leukocytes - immunology; Leukocytes - metabolism; Lung - immunology; Lung - metabolism; Lungs; Macrophages - cytology; Macrophages - immunology; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Mortality; multidisciplinary; NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Orthomyxoviridae Infections - mortality; Orthomyxoviridae Infections - pathology; Pandemics; Pathogenesis; Science; Sulfonylurea Compounds - pharmacology; Survival Rate
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep27912

The inflammasome NLRP3 is activated by pathogen associated molecular patterns (PAMPs) during infection, including RNA and proteins from influenza A virus (IAV). However, chronic activation by danger associated molecular patterns (DAMPs) can be deleterious to the host. We show that blocking NLRP3 activation can be either protective or detrimental at different stages of lethal influenza A virus (IAV). Administration of the specific NLRP3 inhibitor MCC950 to mice from one day following IAV challenge resulted in hypersusceptibility to lethality. In contrast, delaying treatment with MCC950 until the height of disease (a more likely clinical scenario) significantly protected mice from severe and highly virulent IAV-induced disease. These findings identify for the first time that NLRP3 plays a detrimental role later in infection, contributing to IAV pathogenesis through increased cytokine production and lung cellular infiltrates. These studies also provide the first evidence identifying NLRP3 inhibition as a novel therapeutic target to reduce IAV disease severity.