Dectin-1/CARD9 induction of the TFEB and TFE3 gene network is dispensable for phagocyte anti-Aspergillus activity in the lung

Mariano A. Aufiero, Neta Shlezinger, Mergim Gjonbalaj, Kathleen A.M. Mills, Andrea Ballabio, Tobias M. Hohl*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Myeloid phagocytes of the respiratory immune system, such as neutrophils, monocytes, and alveolar macrophages, are essential for immunity to Aspergillus fumigatus, the most common etiologic agent of mold pneumonia worldwide. Following the engulfment of A. fumigatus conidia, fusion of the phagosome with the lysosome is a critical process for killing conidia. TFEB and TFE3 are transcription factors that regulate lysosomal biogenesis under stress and are activated by inflammatory stimuli in macrophages, but it is unknown whether TFEB and TFE3 contribute to anti-Aspergillus immunity during infection. We found that lung neutrophils express TFEB and TFE3, and their target genes were upregulated during A. fumigatus lung infection. In addition, A. fumigatus infection induced nuclear accumulation of TFEB and TFE3 in macrophages in a process regulated by Dectin-1 and CARD9. Genetic deletion of Tfeb and Tfe3 impaired macrophage killing of A. fumigatus conidia. However, in a murine immune-competent Aspergillus infection model with genetic deficiency of Tfeb and Tfe3 in hematopoietic cells, we surprisingly found that lung myeloid phagocytes had no defects in conidial phagocytosis or killing. Loss of TFEB and TFE3 did not impact murine survival or clearance of A. fumigatus from the lungs. Our findings indicate that myeloid phagocytes activate TFEB and TFE3 in response to A. fumigatus, and while this pathway promotes macrophage fungicidal activity in vitro, genetic loss can be functionally compensated in the lung, resulting in no measurable defect in fungal control and host survival.

Original languageAmerican English
JournalInfection and Immunity
Volume91
Issue number11
DOIs
StatePublished - Nov 2023

Bibliographical note

Publisher Copyright:
Copyright © 2023 American Society for Microbiology. All Rights Reserved.

Keywords

  • Aspergillus fumigatus
  • Fungus
  • Innate Immunity
  • Lung
  • Lysosome
  • TFE3
  • TFEB

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