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Nat Microbiol. 2019 Feb;4(2):316-327. doi: 10.1038/s41564-018-0298-0. Epub 2018 Dec 3.

Fungal ligands released by innate immune effectors promote inflammasome activation during Aspergillus fumigatus infection.

Author information

1
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
2
Cellular Imaging Shared Resource, St. Jude Children's Research Hospital, Memphis, TN, USA.
3
Animal Resources Center and the Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, TN, USA.
4
Department of Immunoparasitology, Research Institute for Microbial Diseases, Laboratory of Immunoparasitology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan.
5
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. Thirumala-Devi.Kanneganti@StJude.org.

Abstract

Invasive pulmonary aspergillosis causes substantial mortality in immunocompromised individuals. Recognition of Aspergillus fumigatus by the host immune system leads to activation of the inflammasome, which provides protection against infection. However, regulation of inflammasome activation at the molecular level is poorly understood. Here, we describe two distinct pathways that coordinately control inflammasome activation during A. fumigatus infection. The C-type lectin receptor pathway activates both MAPK and NF-κB signalling, which leads to induction of downstream mediators, such as the transcription factor IRF1, and also primes the inflammasomes. Toll-like receptor signalling through the adaptor molecules MyD88 and TRIF in turn mediates efficient activation of IRF1, which induces IRGB10 expression. IRGB10 targets the fungal cell wall, and the antifungal activity of IRGB10 causes hyphae damage, modifies the A. fumigatus surface and inhibits fungal growth. We also demonstrate that one of the major fungal pathogen-associated molecular patterns, β-glucan, directly triggers inflammasome assembly. Thus, the concerted activation of both Toll-like receptors and C-type lectin receptors is required for IRF1-mediated IRGB10 regulation, which is a key event governing ligand release and inflammasome activation upon A. fumigatus infection.

PMID:
30510167
DOI:
10.1038/s41564-018-0298-0

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