Galactosaminogalactan activates the inflammasome to provide host protection

Benoit Briard, Thierry Fontaine, Parimal Samir, David E. Place, Laetitia Muszkieta, R. K. Subbarao Malireddi, Rajendra Karki, Shelbi Christgen, Perrine Bomme, Peter Vogel, Rémi Beau, Emilia Mellado, Oumaima Ibrahim-Granet, Bernard Henrissat, Ravi C. Kalathur, Cam Robinson, Jean-Paul Latgé and Thirumala-Devi Kanneganti ()
Additional contact information
Benoit Briard: St Jude Children’s Research Hospital
Thierry Fontaine: Unité des Aspergillus, Institut Pasteur
Parimal Samir: St Jude Children’s Research Hospital
David E. Place: St Jude Children’s Research Hospital
Laetitia Muszkieta: Unité des Aspergillus, Institut Pasteur
R. K. Subbarao Malireddi: St Jude Children’s Research Hospital
Rajendra Karki: St Jude Children’s Research Hospital
Shelbi Christgen: St Jude Children’s Research Hospital
Perrine Bomme: Ultrastructural Bio Imaging Unit, C2RT, Institut Pasteur
Peter Vogel: St Jude Children’s Research Hospital
Rémi Beau: Unité des Aspergillus, Institut Pasteur
Emilia Mellado: Centro Nacional de Microbiologia, Instituto de Salud Carlos III
Oumaima Ibrahim-Granet: Unité des Cytokines et Inflammation, Institut Pasteur
Bernard Henrissat: AFMB, UMR 7257 CNRS, Aix-Marseille Université
Ravi C. Kalathur: St Jude Children’s Research Hospital
Cam Robinson: St Jude Children’s Research Hospital
Jean-Paul Latgé: Unité des Aspergillus, Institut Pasteur
Thirumala-Devi Kanneganti: St Jude Children’s Research Hospital

Nature, 2020, vol. 588, issue 7839, 688-692

Abstract: Abstract 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 aspergillosis2,3, 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 (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.

Date: 2020
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DOI: 10.1038/s41586-020-2996-z

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