@article{Herbst:2015:10.15252/emmm.201404556,
author = {Herbst, S and Shah, A and Moya, MM and Marzola, V and Jensen, B and Reed, A and Birrell, MA and Saijo, S and Mostowy, S and Shaunak, S and Armstrong-James, D},
doi = {10.15252/emmm.201404556},
journal = {EMBO Molecular Medicine},
pages = {240--258},
title = {Phagocytosis-dependent activation of a TLR9-BTK-calcineurin-NFAT pathway co-ordinates innate immunity to Aspergillus fumigatus},
url = {http://dx.doi.org/10.15252/emmm.201404556},
volume = {7},
year = {2015}
}

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TY  - JOUR
AB  - 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 NFκB for TNFα production. For yeast zymosan particles, activation of macrophage calcineurin–NFAT occurs via the phagocytic Dectin1–spleen tyrosine kinase pathway, but for A. fumigatus, activation occurs via a phagosomal TLR9dependent and Bruton's tyrosine kinasedependent signalling pathway that is independent of MyD88. We confirm the collaboration between NFAT and NFκB for TNFα 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 transplantrelated invasive aspergillosis.
AU  - Herbst,S
AU  - Shah,A
AU  - Moya,MM
AU  - Marzola,V
AU  - Jensen,B
AU  - Reed,A
AU  - Birrell,MA
AU  - Saijo,S
AU  - Mostowy,S
AU  - Shaunak,S
AU  - Armstrong-James,D
DO  - 10.15252/emmm.201404556
EP  - 258
PY  - 2015///
SN  - 1757-4676
SP  - 240
TI  - Phagocytosis-dependent activation of a TLR9-BTK-calcineurin-NFAT pathway co-ordinates innate immunity to Aspergillus fumigatus
T2  - EMBO Molecular Medicine
UR  - http://dx.doi.org/10.15252/emmm.201404556
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000350767600002&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://www.embopress.org/doi/full/10.15252/emmm.201404556
UR  - http://hdl.handle.net/10044/1/53782
VL  - 7
ER  - 

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