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Repurposing drugs targeting the P2X7 receptor to limit hyperinflammation and disease during influenza virus infection

BACKGROUND AND PURPOSE: Severe influenza A virus (IAV) infections are associated with damaging hyperinflammation that can be fatal. 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 pharmacokine...

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Autores principales: Rosli, Sarah, Kirby, Francis J., Lawlor, Kate E., Rainczuk, Kate, Drummond, Grant R., Mansell, Ashley, Tate, Michelle D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780046/
https://www.ncbi.nlm.nih.gov/pubmed/31271646
http://dx.doi.org/10.1111/bph.14787
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author Rosli, Sarah
Kirby, Francis J.
Lawlor, Kate E.
Rainczuk, Kate
Drummond, Grant R.
Mansell, Ashley
Tate, Michelle D.
author_facet Rosli, Sarah
Kirby, Francis J.
Lawlor, Kate E.
Rainczuk, Kate
Drummond, Grant R.
Mansell, Ashley
Tate, Michelle D.
author_sort Rosli, Sarah
collection PubMed
description BACKGROUND AND PURPOSE: Severe influenza A virus (IAV) infections are associated with damaging hyperinflammation that can be fatal. 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‐dependent roles during severe IAV infection with early protective responses and later dysregulation leading to excessive inflammation, contributing to disease severity. EXPERIMENTAL APPROACH: 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‐dependent IL‐1β secretion in macrophage cultures. In vivo, their effects were assessed on hyperinflammation and disease during severe IAV infection in C57BL/6 mice. KEY RESULTS: Treatment of macrophages with probenecid or AZ11645373 in vitro diminished NLRP3 inflammasome‐dependent IL‐1β secretion. Intranasal therapeutic treatment of mice displaying severe influenza disease with probenecid or AZ11645373 reduced pro‐inflammatory 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. CONCLUSIONS AND IMPLICATIONS: Our study demonstrates that the anti‐inflammatory 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.
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spelling pubmed-67800462019-10-11 Repurposing drugs targeting the P2X7 receptor to limit hyperinflammation and disease during influenza virus infection Rosli, Sarah Kirby, Francis J. Lawlor, Kate E. Rainczuk, Kate Drummond, Grant R. Mansell, Ashley Tate, Michelle D. Br J Pharmacol Research Papers BACKGROUND AND PURPOSE: Severe influenza A virus (IAV) infections are associated with damaging hyperinflammation that can be fatal. 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‐dependent roles during severe IAV infection with early protective responses and later dysregulation leading to excessive inflammation, contributing to disease severity. EXPERIMENTAL APPROACH: 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‐dependent IL‐1β secretion in macrophage cultures. In vivo, their effects were assessed on hyperinflammation and disease during severe IAV infection in C57BL/6 mice. KEY RESULTS: Treatment of macrophages with probenecid or AZ11645373 in vitro diminished NLRP3 inflammasome‐dependent IL‐1β secretion. Intranasal therapeutic treatment of mice displaying severe influenza disease with probenecid or AZ11645373 reduced pro‐inflammatory 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. CONCLUSIONS AND IMPLICATIONS: Our study demonstrates that the anti‐inflammatory 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. John Wiley and Sons Inc. 2019-08-19 2019-10 /pmc/articles/PMC6780046/ /pubmed/31271646 http://dx.doi.org/10.1111/bph.14787 Text en © 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research Papers
Rosli, Sarah
Kirby, Francis J.
Lawlor, Kate E.
Rainczuk, Kate
Drummond, Grant R.
Mansell, Ashley
Tate, Michelle D.
Repurposing drugs targeting the P2X7 receptor to limit hyperinflammation and disease during influenza virus infection
title Repurposing drugs targeting the P2X7 receptor to limit hyperinflammation and disease during influenza virus infection
title_full Repurposing drugs targeting the P2X7 receptor to limit hyperinflammation and disease during influenza virus infection
title_fullStr Repurposing drugs targeting the P2X7 receptor to limit hyperinflammation and disease during influenza virus infection
title_full_unstemmed Repurposing drugs targeting the P2X7 receptor to limit hyperinflammation and disease during influenza virus infection
title_short Repurposing drugs targeting the P2X7 receptor to limit hyperinflammation and disease during influenza virus infection
title_sort repurposing drugs targeting the p2x7 receptor to limit hyperinflammation and disease during influenza virus infection
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780046/
https://www.ncbi.nlm.nih.gov/pubmed/31271646
http://dx.doi.org/10.1111/bph.14787
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