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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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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. |
format | Online Article Text |
id | pubmed-6780046 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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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