title: 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 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.
authors: Department of Infectious Diseases and Immunity, Imperial College London, London, UK.
authors: Susanne
authors: S
authors: Herbst
authors: Department of Infectious Diseases and Immunity, Imperial College London, London, UK.
authors: Anand
authors: A
authors: Shah
authors: MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, UK.
authors: Maria
authors: M
authors: Mazon Moya
authors: Department of Infectious Diseases and Immunity, Imperial College London, London, UK.
authors: Vanessa
authors: V
authors: Marzola
authors: Department of Infectious Diseases and Immunity, Imperial College London, London, UK.
authors: Barbara
authors: B
authors: Jensen
authors: Lung Transplant Unit, Royal Brompton and Harefield Hospital, London, UK.
authors: Anna
authors: A
authors: Reed
authors: National Heart and Lung Institute, Imperial College London, London, UK.
authors: Mark A
authors: MA
authors: Birrell
authors: Medical Mycology Research Centre, Chiba University, Chiba, Japan.
authors: Shinobu
authors: S
authors: Saijo
authors: MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, UK.
authors: Serge
authors: S
authors: Mostowy
authors: Department of Infectious Diseases and Immunity, Imperial College London, London, UK.
authors: Sunil
authors: S
authors: Shaunak
authors: Department of Infectious Diseases and Immunity, Imperial College London, London, UK National Heart and Lung Institute, Imperial College London, London, UK d.armstrong@imperial.ac.uk.
authors: Darius
authors: D
authors: Armstrong-James
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001228:Aspergillosis / Q000276:immunology / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000276:immunology*; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D007113:Immunity, Innate; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010587:Phagocytosis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D016559:Tacrolimus / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015027:Zebrafish
chemical_list: D065095:Calcineurin Inhibitors; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; D019703:Calcineurin; D016559:Tacrolimus
keywords: TLR9; aspergillus; calcineurin; phagocytosis; transplant
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