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There is an urgent need to identify new therapeutic agents to treat severe and pathogenic IAV infections. Repurposing of drugs with an existing and studied pharmacokinetic and safety profile is a highly attractive potential strategy. We have previously demonstrated that the NLRP3 inflammasome plays time\u2010dependent roles during severe IAV infection with early protective responses and later dysregulation leading to excessive inflammation, contributing to disease severity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We tested two existing drugs, probenecid and AZ11645373, to target P2X7 receptor signalling and dampen NLRP3 inflammasome responses during severe IAV infection. In vitro, the drugs were assessed for their ability to limit NLRP3 inflammasome\u2010dependent IL\u20101\u03b2 secretion in macrophage cultures. In vivo, their effects were assessed on hyperinflammation and disease during severe IAV infection in C57BL\/6 mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Treatment of macrophages with probenecid or AZ11645373 in vitro diminished NLRP3 inflammasome\u2010dependent IL\u20101\u03b2 secretion. Intranasal therapeutic treatment of mice displaying severe influenza disease with probenecid or AZ11645373 reduced pro\u2010inflammatory cytokine production, cellular infiltrates in the lung, and provided protection against disease. Importantly, these drugs could be administered at either early or late stage of disease and provide therapeutic efficacy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Our study demonstrates that the anti\u2010inflammatory drugs probenecid and AZ11645373, which have documented pharmacokinetics and safety profiles in humans, are effective at dampening hyperinflammation and severe influenza disease providing potentially new therapeutic strategies for treating severe or pathogenic IAV infections.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14787","type":"journal-article","created":{"date-parts":[[2019,7,4]],"date-time":"2019-07-04T18:23:33Z","timestamp":1562264613000},"page":"3834-3844","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["Repurposing drugs targeting the <scp>P2X7<\/scp> receptor to limit hyperinflammation and disease during influenza virus infection"],"prefix":"10.1111","volume":"176","author":[{"given":"Sarah","family":"Rosli","sequence":"first","affiliation":[{"name":"Centre for Innate Immunity and Infectious Diseases Hudson Institute of Medical Research  Clayton Victoria Australia"},{"name":"Department of Molecular and Translational Sciences Monash University  Clayton Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis J.","family":"Kirby","sequence":"additional","affiliation":[{"name":"Centre for Innate Immunity and Infectious Diseases Hudson Institute of Medical Research  Clayton Victoria Australia"},{"name":"Department of Molecular and Translational Sciences Monash University  Clayton Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate E.","family":"Lawlor","sequence":"additional","affiliation":[{"name":"Centre for Innate Immunity and Infectious Diseases Hudson Institute of Medical Research  Clayton Victoria Australia"},{"name":"Department 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