Inflammasomes are important sentinels of innate immune defence that are activated in response to diverse stimuli, including pathogen-associated molecular patterns (PAMPs). Activation of the inflammasome provides host defence against aspergillosis, which is a major health concern for patients who are immunocompromised. However, the Aspergillus fumigatus PAMPs that are responsible for inflammasome activation are not known. Here we show that the polysaccharide galactosaminogalactan (GAG) of A. fumigatus is a PAMP that activates the NLRP3 inflammasome. The binding of GAG to ribosomal proteins inhibited cellular translation machinery, and thus activated the NLRP3 inflammasome. The galactosamine moiety bound to ribosomal proteins and blocked cellular translation, which triggered activation of the NLRP3 inflammasome. In mice, a GAG-deficient Aspergillus mutant (Δgt4c) did not elicit protective activation of the inflammasome, and this strain exhibited enhanced virulence. Moreover, administration of GAG protected mice from colitis induced by dextran sulfate sodium in an inflammasome-dependent manner. Thus, ribosomes connect the sensing of this fungal PAMP to the activation of an innate immune response.
binding, PAMP, Aspergillus fumigatus, galactosaminogalactan, NLRP3 inflammasome
NCBI PubMed ID: 33268895Publication DOI: 10.1038/s41586-020-2996-zJournal NLM ID: 0410462Publisher: Basingstoke: Nature Publishing Group
Correspondence: Thirumala-Devi.Kanneganti@StJude.org
Institutions: Unité des Aspergillus, Institut Pasteur, Paris, France, Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA, Ultrastructural Bio Imaging Unit, C2RT, Institut Pasteur, Paris, France, Animal Resources Center and the Veterinary Pathology Core, St Jude Children's Research Hospital, Memphis, TN, USA, Mycology Reference Laboratory, Centro Nacional de Microbiologia, Instituto de Salud Carlos III, Madrid, Spain, Unité des Cytokines et Inflammation, Institut Pasteur, Paris, France, AFMB, UMR 7257 CNRS, Aix-Marseille Université, Marseille, France, Department of Biological Sciences, King Abdulaziz University, Jeddah, Saudi Arabia, Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN, USA, Cell and Tissue Imaging Center, St Jude Children's Research Hospital, Memphis, TN, USA, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Heraklion, Greece
Methods: methylation, deacetylation, PCR, GC-MS, acid hydrolysis, GLC, biological assays, MS, immunoblotting, acetylation, cloning, reduction, cell growth, immunofluorescence microscopy, cytokine production, adhesion assays, precipitation, phenol-sulfuric acid assay, spectrophotometry, SEM, centrifugation, qRT-PCR, filtration
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