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Galactosaminogalactan activates the inflammasome to provide host protection

A Publisher Correction to this article was published on 21 December 2020

This article has been updated

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.

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Fig. 1: Aspergillus fumigatus GT4C regulates GAG synthesis.
Fig. 2: GT4C potentiates A.-fumigatus-induced inflammasome activation.
Fig. 3: The galactosamine of GAG interacts with ribosomes, inhibits translation and induces NLRP3 inflammasome activation.
Fig. 4: GAG-induced activation of the inflammasome provides host protection against aspergillosis and DSS-induced colitis.

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Data availability

The datasets generated and analysed in this study are contained within the Article, and its Supplementary Information; any other relevant data are available from the corresponding author upon reasonable request. Source data are provided with this paper.

Change history

  • 21 December 2020

    A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-03088-5

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Acknowledgements

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).

Author information

Authors and Affiliations

Authors

Contributions

B.B. and T.-D.K. conceptualized the study and designed the experiments. B.B., P.S., D.E.P., R.K.S.M., R.K. and S.C. performed the in vitro experiments with BMDMs. B.B., D.E.P., R.K. and S.C. performed the in vivo experiments. T.F., L.M., P.B., R.B., E.M., O.I.-G. and B.H. generated and biochemically characterized the Δgt4c Aspergillus strain. P.V. analysed the in vivo pathology. B.B., P.S. and R.C.K. performed the polysome profiling. P.B. and C.R. performed the electron microscopy. B.B., T.F., J.-P.L. and T.-D.K. analysed the data. B.B. and T.-D.K. wrote the paper. T.-D.K. and J.-P.L. obtained funding. T.-D.K. supervised the study.

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Correspondence to Thirumala-Devi Kanneganti.

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Peer review information Nature thanks Gordon D. Brown, Osamu Takeuchi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Fig. 1 Identification of A. fumigatus GAG synthase.

a, Schematic of GAG synthase cluster. b, RNA sequencing analysis during A. fumigatus growth (0, 4 and 8 h) from ref. 46; gene expression is represented by mean of normalized read count per gene for the GT4C cluster. n = 3 biologically independent samples. Data are mean ± s.e.m. c, Heat map showing differential gene expression of A. fumigatus at 4 h (swollen conidia) and 8 h (germinated conidia) compared to 0 h (resting conidia). d, Schematic of the GT4C protein with transmembrane regions (black), α-glycosyltransferase domains (green) and major facilitator superfamily domain (MFS) predicted from amino acid sequence with InterProscan 5. e, Schematic of wild-type (WT) and Δgt4c locus with NcoI restriction sites and Southern blot probe used to control the GT4C gene deletion. f, Southern blot using GT4C probe with WT and Δgt4c purified DNA from one experiment. g, RT–PCR analysis of GT4C, AGD3, EGA3, SPH3 and UGE3 A. fumigatus genes in WT and Δgt4c strains (8 h in LB medium, 37 °C and 250 rpm) presented relative to that of TEF1. n.d., not detected. n = 3 biologically independent samples. Data are mean ± s.e.m.

Source data

Extended Data Fig. 2 Absence of GAG does not affect release of non-inflammasome dependent cytokines.

a, b, Release of IL-6 (a) and TNF (b) from unprimed BMDMs left uninfected (med.) or assessed 20 h after infection with A. fumigatus wild type (WT) or Δgt4c strain (MOI of 10). n = 3 independent biological samples. Data are mean ± s.e.m.

Source data

Extended Data Fig. 3 UGE3 potentiates A.-fumigatus-induced inflammasome activation.

a, Assessment of biofilm formation on an abiotic surface with A. fumigatus (A. f) wild type (WT) and deletion mutant strain Δuge3. b, Immunoblot analysis of pro-caspase 1 (pro-Casp1; p45) and the active caspase 1 subunit (p20) from unprimed BMDMs left untreated (medium alone (med.)) or measured 20 h after infection with the indicated A. fumigatus live resting conidia (MOI of 10). Representative images. n ≥ 3 independent experiments. c, Immunoblot analysis of phospho-IκBα and total IκBα (t-IκBα) or phospho-ERK1/2 (p-ERK) and total ERK1/2 (t-ERK) from unprimed WT BMDMs 0–8 h after infection with WT or Δuge3 mutant A. fumigatus live resting conidia (MOI of 10). Representative images. n ≥ 3 independent experiments. d, Immunoblot analysis of pro-IL-1β from unprimed BMDMs 0–8 h after infection with WT or Δuge3 mutant A. fumigatus live resting conidia (MOI of 10). Representative images. n ≥ 3 independent experiments. eg, RT–PCR analysis of Nlrp3, Il1b and Tnf genes from WT BMDMs 0–8 h after infection with WT or Δuge3 mutant A. fumigatus live resting conidia presented relative to that of the gene encoding β-actin. n = 4 biologically independent samples. Data are mean ± s.e.m.

Source data

Extended Data Fig. 4 Over-synthesis of GAG induces hyper-inflammasome activation.

a, Immunofluorescence staining of A. fumigatus GAG (green) and BMDM nuclei (blue) in unprimed BMDMs 4 h after infection with A. fumigatus wild-type (WT) or Δugm1 resting conidia (MOI of 10). Scale bars, 10 μm. Representative images. n ≥ 3 independent experiments. b, Immunoblot analysis of pro-caspase 1 (pro-Casp1; p45) and the active caspase 1 subunit (p20) of unprimed BMDMs left untreated (medium alone (med.)) or assessed 20 h after infection with the indicated live A. fumigatus resting conidia genotype (WT or A. fumigatus deletion mutant Δugm1) (MOI of 10). Representative image. n ≥ 3 independent experiments. c, Release of IL-1β from unprimed BMDMs left uninfected (med.) or assessed 20 h after infection with A. fumigatus (MOI of 10). **P = 0.0046. Unpaired two-tailed t-test. n = 4 biologically independent samples. Data are mean ± s.e.m.

Source data

Extended Data Fig. 5 GAG induces caspase 1 cleavage in a dose- and charge–charge interaction-dependent manner and interacts with ribosomes.

a, Representative images of BMDMs in medium (med.) or during treatment with DOTAP alone (green fluorescence corresponds to Sytox green nuclei, and Sytox green-positive nuclei are marked with a red circle). Scale bars, 10 μm. Representative images. n ≥ 3 independent experiments. b, Immunoblot analysis of pro-caspase 1 (pro-Casp1; p45) and the active caspase 1 subunit (p20) of BMDMs left untreated (medium alone (med.)) or assessed 3 h after transfection with increasing concentrations of GAG or vehicle alone (DOTAP). Representative image. n ≥ 3 independent experiments. c, Immunoblot analysis of caspase 1 during transfection with GAG in wild-type (WT) and Gsdmd−/− BMDMs. Representative image. n ≥ 3 independent experiments. d, Volcano plot of the polysaccharide pull-down mass spectrometry analysis of the β-glucan interactome with BMDM cytosolic proteins versus control. Proteins with P < 0.005 are highlighted in orange and proteins with P < 0.005 and log2-transformed fold change > 7 compared to control are highlighted in red (none identified); P value was determined by the G test; exact P values are presented in Supplementary Table 1. e, Immunoblot analysis of ribosomal proteins interacting with GAG, Ac-GAG, d-GAG or β-glucan or vehicle with or without NaCl. Representative images. n ≥ 3 independent experiments. f, Immunoblot analysis of caspase 1 from BMDMs assessed after 3 h incubation with GAG, Ac-GAG or d-GAG, with or without NaCl. Representative image. n ≥ 3 independent experiments. g, h, Measurement of cell death by Sytox green staining during GAG and d-GAG treatment, with or without NaCl. n = 3 biologically independent samples. Data are mean ± s.e.m. i, Electron microscopy pictures of ribosomes, GAG + ribosomes and chitin + ribosomes with negative staining; data from one experiment. Scale bars, 100 nm.

Source data

Extended Data Fig. 6 GAG inhibits translation and induces endoplasmic stress.

ac Immunoblot analysis of translation rate in BMDMs by puromycin integration into proteins during vehicle (DOTAP) or PBS incubation (a), poly(dA:dT) transfection (b) or A. fumigatus infection and pro-caspase 1 (pro-Casp1; p45) and the active caspase 1 subunit (p20) during A. fumigatus infection (c). Representative images. n ≥ 2 independent experiments. d, Polysome profiling during DOTAP or DOTAP + GAG treatments. e, Immunoblot analysis of the cell pellet after polysome profiling. Representative images. n ≥ 2 independent experiments. f, Polysome:monosome ratio during DOTAP or DOTAP + GAG treatments. Data are mean ± s.e.m. *P = 0.0366. Paired two-tailed t-test. n = 3 biologically independent samples. gi, Immunoblot analysis of pro-caspase 1 and the active caspase 1 subunit of wild-type (WT) or Nlrp3−/− BMDMs assessed after 16 h incubation with 25 μg ml−1 anisomycin (aniso) (g), 50 μg ml−1 puromycin (puro) (h) or 50 μg ml−1 cycloheximide (CHX) (i). Representative images. n ≥ 2 independent experiments. j, k, Immunoblot analysis of PERK activation (p-PERK) and IRE1α induction during GAG transfection (j) or PERK activation during treatment with translation inhibitors (k). Representative images. n ≥ 2 independent experiments. l, Immunoblot analysis of proteins ubiquitinated during GAG transfection. Representative images. n ≥ 2 independent experiments. m, Immunoblot analysis of caspase 1 of BMDMs left untreated (medium alone (med.)) or assessed 3 h after transfection with DOTAP alone, GAG or GAG with MG132 treatment. Representative image. n ≥ 2 independent experiments.

Source data

Extended Data Fig. 7 Stress granules are not induced by GAG.

a, Immunofluorescence staining of G3BP1 (green), DDX3X (red) and BMDM nuclei (blue) in unprimed BMDMs 40 min after transfection with GAG or incubation with arsenite (Ars). Representative images. n ≥ 2 independent experiments. b, Quantification of the percentage of stress-granule-positive cells after transfection with GAG, vehicle (DOTAP) alone or Ars. n > 10 biologically independent fields of cells. Data are mean ± s.e.m. c, Immunofluorescence staining of G3BP1 (green), DDX3X (red) and BMDM nuclei (blue) in unprimed BMDMs 15 h after infection with A. fumigatus. Representative images. n ≥ 2 independent experiments. d, e, Immunoblot analysis of pro-caspase 1 (pro-Casp1; p45) and the active caspase 1 subunit (p20) of BMDMs assessed 3 h after transfection with vehicle (DOTAP), GAG (d) or d-GAG (e). Representative images. n ≥ 2 independent experiments. f, Immunoblot analysis of caspase 1 from BMDMs left untreated (medium alone (med.)) or infected with A. fumigatus wild-type (WT) or deletion mutant ∆gt4c (MOI of 10). Representative image. n ≥ 2 independent experiments. Scale bars, 10 μm (a, c).

Source data

Extended Data Fig. 8 GAG-induced pro-inflammatory cytokine secretion during aspergillosis and DSS-induced colitis.

a, b, Level of IL-1β (a) and IL-18 (b) in bronchioalveolar lavage 2 days after infection with wild-type (WT) or Δugm1 strains of A. fumigatus. a, *P = 0.036. Unpaired two-tailed t-test. n = 6 independent samples. Data are mean ± s.e.m. c, Survival of 7–8-week-old immunocompetent WT mice infected intravenously with 1 × 106 A. fumigatus resting conidia (WT or Δugm1). **P = 0.0014. Log-rank (Mantel–Cox) test. d, e, Levels of IL-1β (d) and IL-18 (e) in liver homogenates after infection with WT or Δgt4c strains. d, *P = 0.0209; e, **P = 0.0041. Unpaired two-tailed t-test. n = 5 independent samples. Data are mean ± s.e.m. fk, Concentration of cytokines in colon homogenates after DSS water supplementation and treatment with GAG or vehicle (vehicle and GAG, n = 10 mice each). f, *P = 0.0336; g, *P = 0.0181; h, *P = 0.0188; i, *P = 0.0115; j, **P = 0.0066; k, *P = 0.0154. Unpaired two-tailed t-test. Data are mean ± s.e.m.

Source data

Extended Data Table 1 Primer list
Extended Data Table 2 Exact P values

Supplementary information

Supplementary Table

Supplementary Table 1: Spectral count comparison of proteins identified from the Control and GAG-treated samples. P values were determined by the G-test.

Reporting Summary

Supplementary Figure

Supplementary Figure 1: Uncropped blots with molecular weight and size markers and an indication of how the images were cropped.

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Briard, B., Fontaine, T., Samir, P. et al. Galactosaminogalactan activates the inflammasome to provide host protection. Nature 588, 688–692 (2020). https://doi.org/10.1038/s41586-020-2996-z

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