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

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.

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Fig. 1: Downstream adaptors of TLRs and CLRs are required for inflammasome activation during A.fumigatus infection.
Fig. 2: The SYK–CARD9–MALT1 complex regulates IRF1 expression, whereas the activation of IRF1 is MyD88–TRIF dependent.
Fig. 3: IRF1 regulates the expression of GBPs and IRGB10 upon A.fumigatus infection.
Fig. 4: IRGB10, but not GBPs, contributes to the activation of inflammasomes in response to A.fumigatus.
Fig. 5: IRGB10 targets intracellular A.fumigatus, and IRGB10 peptides inhibit A.fumigatus growth and release fungal ligands that induce inflammasome activation.
Fig. 6: IRGB10 provides host protection against infection with A.fumigatus in vivo.

Data availability

The data that support the findings of this study are available from the corresponding author upon request.

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Acknowledgements

We thank members of the Kanneganti lab, the St. Jude Children’s Hospital Veterinary Pathology Core, Macromolecular Synthesis Core and Electron Microscopy Core. Images were acquired at the SJCRH Cell & Tissue Imaging Center, which is supported by SJCRH and NCI P30 CA021765–35. Work from our laboratories is supported by the US NIH (AI101935, AI124346, AR056296 and CA163507 to T.-D.K.) and the American Lebanese Syrian Associated Charities (to T.-D.K.). M.Y. is supported by the Research Program on Emerging and Re-emerging Infectious Diseases (18fk0108047h0002) and Japanese Initiative for Progress of Research on Infectious Diseases for Global Epidemic (18fm0208018h0002) from the Agency for Medical Research and Development.

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B.B., R.K., R.K.S.M., J.M., A.B., D.E.P. and J.L.P. performed the experiments. B.B., R.K., R.K.S.M., P.V., M.Y. and T.-D.K. analysed the data. B.B., A.B. and R.K. wrote the paper. T.-D.K. oversaw the project and funding.

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Correspondence to Thirumala-Devi Kanneganti.

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Briard, B., Karki, R., Malireddi, R.K.S. et al. Fungal ligands released by innate immune effectors promote inflammasome activation during Aspergillus fumigatus infection. Nat Microbiol 4, 316–327 (2019). https://doi.org/10.1038/s41564-018-0298-0

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