Galactosaminogalactan activates the inflammasome to provide host protection

Autor: Emilia Mellado, Jean-Paul Latgé, Parimal Samir, Shelbi Christgen, Thierry Fontaine, Cam Robinson, R. K. Subbarao Malireddi, Rajendra Karki, Laetitia Muszkieta, David E. Place, Perrine Bomme, Rémi Beau, Ravi C. Kalathur, Thirumala-Devi Kanneganti, Oumaïma Ibrahim-Granet, Benoit Briard, Bernard Henrissat, Peter Vogel
Přispěvatelé: St. Jude Children’s Research Hospital [Memphis], Aspergillus, Institut Pasteur [Paris], Plateforme BioImagerie Ultrastructurale – Ultrastructural BioImaging Platform (UTechS UBI), Instituto de Salud Carlos III [Madrid] (ISC), Cytokines et Inflammation, Architecture et fonction des macromolécules biologiques (AFMB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), King Abdulaziz University, We thank members of the Kanneganti laboratory for their comments, suggestions and technical assistance, R. Tweedell for scientific editing of the manuscript, the St Jude Children’s Research Hospital Veterinary Pathology Core, SJCRH Center for Proteomics and Metabolomics and SJCRH Cell and Tissue Imaging Center (supported by the NCI P30 CA021765), D. Sheppard for sharing the A. fumigatus deletion mutant ∆agd, and V. M. Dixit and N. Kayagaki for the Casp1−/−Casp11−/− mutant mouse strain. T.-D.K. is supported by NIH grants AI101935, AI124346, AR056296 and CA253095 and by the American Lebanese Syrian Associated Charities. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. J.-P.L. is supported by the Aviesan project Aspergillus, the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence ‘Integrative Biology of Emerging Infectious Diseases’ (grant number ANR-10-LABX-62-IBEID) and la Fondation pour la Recherche Médicale (DEQ20150331722 LATGE Equipe FRM 2015)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), St Jude Children's Research Hospital, Institut Pasteur [Paris] (IP)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Nature
Nature, Nature Publishing Group, 2020, 588 (7839), pp.688-692. ⟨10.1038/s41586-020-2996-z⟩
Nature, 2020, 588 (7839), pp.688-692. ⟨10.1038/s41586-020-2996-z⟩
ISSN: 0028-0836
1476-4679
1476-4687
DOI: 10.1038/s41586-020-2996-z⟩
Popis: International audience; Galactosaminogalactan of Aspergillus fumigatus acts as a pathogen-associated molecular pattern that activates the NLRP3 inflammasome, which is crucial for anti-fungal host defence.Inflammasomes are important sentinels of innate immune defence that are activated in response to diverse stimuli, including pathogen-associated molecular patterns (PAMPs)(1). Activation of the inflammasome provides host defence against aspergillosis(2,3), 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 (Delta gt4c) 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.
Databáze: OpenAIRE
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