Corticosteroids block autophagy protein recruitment in Aspergillus fumigatus phagosomes via targeting dectin-1/Syk kinase signaling

J Immunol. 2013 Aug 1;191(3):1287-99. doi: 10.4049/jimmunol.1300132. Epub 2013 Jul 1.

Abstract

Aspergillus fumigatus is the predominant airborne fungal pathogen in immunocompromised patients. Genetic defects in NADPH oxidase (chronic granulomatous disease [CGD]) and corticosteroid-induced immunosupression lead to impaired killing of A. fumigatus and unique susceptibility to invasive aspergillosis via incompletely characterized mechanisms. Recent studies link TLR activation with phagosome maturation via the engagement of autophagy proteins. In this study, we found that infection of human monocytes with A. fumigatus spores triggered selective recruitment of the autophagy protein LC3 II in phagosomes upon fungal cell wall swelling. This response was induced by surface exposure of immunostimulatory β-glucans and was mediated by activation of the Dectin-1 receptor. LC3 II recruitment in A. fumigatus phagosomes required spleen tyrosine kinase (Syk) kinase-dependent production of reactive oxygen species and was nearly absent in monocytes of patients with CGD. This pathway was important for control of intracellular fungal growth, as silencing of Atg5 resulted in impaired phagosome maturation and killing of A. fumigatus. In vivo and ex vivo administration of corticosteroids blocked LC3 II recruitment in A. fumigatus phagosomes via rapid inhibition of phosphorylation of Src and Syk kinases and downstream production of reactive oxygen species. Our studies link Dectin-1/Syk kinase signaling with autophagy-dependent maturation of A. fumigatus phagosomes and uncover a potential mechanism for development of invasive aspergillosis in the setting of CGD and corticosteroid-induced immunosupression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex Hormones / metabolism
  • Adrenal Cortex Hormones / pharmacology
  • Aged
  • Aspergillosis / immunology
  • Aspergillus fumigatus / immunology*
  • Autophagy / immunology*
  • Autophagy-Related Protein 5
  • Cells, Cultured
  • Female
  • Granulomatous Disease, Chronic / immunology
  • Granulomatous Disease, Chronic / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lectins, C-Type / metabolism*
  • Leukocytes, Mononuclear / immunology*
  • Microtubule-Associated Proteins / drug effects
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Middle Aged
  • Phagosomes / immunology
  • Phagosomes / microbiology
  • Phosphorylation / drug effects
  • Protein-Tyrosine Kinases / metabolism*
  • RNA Interference
  • RNA, Small Interfering
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Syk Kinase
  • src-Family Kinases / metabolism

Substances

  • ATG5 protein, human
  • Adrenal Cortex Hormones
  • Autophagy-Related Protein 5
  • CLEC7A protein, human
  • Intracellular Signaling Peptides and Proteins
  • Lectins, C-Type
  • MAP1LC3A protein, human
  • Microtubule-Associated Proteins
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase
  • src-Family Kinases