Phagocytosis‐dependent activation of a TLR9–BTK–calcineurin–NFAT pathway co‐ordinates innate immunity to Aspergillus fumigatus
Abstract Transplant recipients on calcineurin inhibitors are at high risk of invasive fungal infection. Understanding how calcineurin inhibitors impair fungal immunity is a key priority for defining risk of infection. Here, we show that the calcineurin inhibitor tacrolimus impairs clearance of the m...
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| Format: | Article |
| Language: | English |
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Springer Nature
2015-01-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201404556 |
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| author | Susanne Herbst Anand Shah Maria Mazon Moya Vanessa Marzola Barbara Jensen Anna Reed Mark A Birrell Shinobu Saijo Serge Mostowy Sunil Shaunak Darius Armstrong‐James |
| author_facet | Susanne Herbst Anand Shah Maria Mazon Moya Vanessa Marzola Barbara Jensen Anna Reed Mark A Birrell Shinobu Saijo Serge Mostowy Sunil Shaunak Darius Armstrong‐James |
| author_sort | Susanne Herbst |
| collection | DOAJ |
| description | Abstract Transplant recipients on calcineurin inhibitors are at high risk of invasive fungal infection. Understanding how calcineurin inhibitors impair fungal immunity is a key priority for defining risk of infection. Here, we show that the calcineurin inhibitor tacrolimus impairs clearance of the major mould pathogen Aspergillus fumigatus from the airway, by inhibiting macrophage inflammatory responses. This leads to defective early neutrophil recruitment and fungal clearance. We confirm these findings in zebrafish, showing an evolutionarily conserved role for calcineurin signalling in neutrophil recruitment during inflammation. We find that calcineurin–NFAT activation is phagocytosis dependent and collaborates with NF‐κB for TNF‐α production. For yeast zymosan particles, activation of macrophage calcineurin–NFAT occurs via the phagocytic Dectin‐1–spleen tyrosine kinase pathway, but for A. fumigatus, activation occurs via a phagosomal TLR9‐dependent and Bruton's tyrosine kinase‐dependent signalling pathway that is independent of MyD88. We confirm the collaboration between NFAT and NF‐κB for TNF‐α production in primary alveolar macrophages. These observations identify inhibition of a newly discovered macrophage TLR9–BTK–calcineurin–NFAT signalling pathway as a key immune defect that leads to organ transplant‐related invasive aspergillosis. |
| format | Article |
| id | doaj-art-13031244d16d4b3ba809b9ade5152b6d |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2015-01-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-13031244d16d4b3ba809b9ade5152b6d2025-08-20T03:05:55ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842015-01-017324025810.15252/emmm.201404556Phagocytosis‐dependent activation of a TLR9–BTK–calcineurin–NFAT pathway co‐ordinates innate immunity to Aspergillus fumigatusSusanne Herbst0Anand Shah1Maria Mazon Moya2Vanessa Marzola3Barbara Jensen4Anna Reed5Mark A Birrell6Shinobu Saijo7Serge Mostowy8Sunil Shaunak9Darius Armstrong‐James10Department of Infectious Diseases and Immunity, Imperial College LondonDepartment of Infectious Diseases and Immunity, Imperial College LondonMRC Centre for Molecular Bacteriology and Infection, Imperial College LondonDepartment of Infectious Diseases and Immunity, Imperial College LondonDepartment of Infectious Diseases and Immunity, Imperial College LondonLung Transplant Unit, Royal Brompton and Harefield HospitalNational Heart and Lung Institute, Imperial College LondonMedical Mycology Research Centre, Chiba UniversityMRC Centre for Molecular Bacteriology and Infection, Imperial College LondonDepartment of Infectious Diseases and Immunity, Imperial College LondonDepartment of Infectious Diseases and Immunity, Imperial College LondonAbstract Transplant recipients on calcineurin inhibitors are at high risk of invasive fungal infection. Understanding how calcineurin inhibitors impair fungal immunity is a key priority for defining risk of infection. Here, we show that the calcineurin inhibitor tacrolimus impairs clearance of the major mould pathogen Aspergillus fumigatus from the airway, by inhibiting macrophage inflammatory responses. This leads to defective early neutrophil recruitment and fungal clearance. We confirm these findings in zebrafish, showing an evolutionarily conserved role for calcineurin signalling in neutrophil recruitment during inflammation. We find that calcineurin–NFAT activation is phagocytosis dependent and collaborates with NF‐κB for TNF‐α production. For yeast zymosan particles, activation of macrophage calcineurin–NFAT occurs via the phagocytic Dectin‐1–spleen tyrosine kinase pathway, but for A. fumigatus, activation occurs via a phagosomal TLR9‐dependent and Bruton's tyrosine kinase‐dependent signalling pathway that is independent of MyD88. We confirm the collaboration between NFAT and NF‐κB for TNF‐α production in primary alveolar macrophages. These observations identify inhibition of a newly discovered macrophage TLR9–BTK–calcineurin–NFAT signalling pathway as a key immune defect that leads to organ transplant‐related invasive aspergillosis.https://doi.org/10.15252/emmm.201404556aspergilluscalcineurinphagocytosisTLR9transplant |
| spellingShingle | Susanne Herbst Anand Shah Maria Mazon Moya Vanessa Marzola Barbara Jensen Anna Reed Mark A Birrell Shinobu Saijo Serge Mostowy Sunil Shaunak Darius Armstrong‐James Phagocytosis‐dependent activation of a TLR9–BTK–calcineurin–NFAT pathway co‐ordinates innate immunity to Aspergillus fumigatus EMBO Molecular Medicine aspergillus calcineurin phagocytosis TLR9 transplant |
| title | Phagocytosis‐dependent activation of a TLR9–BTK–calcineurin–NFAT pathway co‐ordinates innate immunity to Aspergillus fumigatus |
| title_full | Phagocytosis‐dependent activation of a TLR9–BTK–calcineurin–NFAT pathway co‐ordinates innate immunity to Aspergillus fumigatus |
| title_fullStr | Phagocytosis‐dependent activation of a TLR9–BTK–calcineurin–NFAT pathway co‐ordinates innate immunity to Aspergillus fumigatus |
| title_full_unstemmed | Phagocytosis‐dependent activation of a TLR9–BTK–calcineurin–NFAT pathway co‐ordinates innate immunity to Aspergillus fumigatus |
| title_short | Phagocytosis‐dependent activation of a TLR9–BTK–calcineurin–NFAT pathway co‐ordinates innate immunity to Aspergillus fumigatus |
| title_sort | phagocytosis dependent activation of a tlr9 btk calcineurin nfat pathway co ordinates innate immunity to aspergillus fumigatus |
| topic | aspergillus calcineurin phagocytosis TLR9 transplant |
| url | https://doi.org/10.15252/emmm.201404556 |
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