Corticosteroids Block Autophagy Protein Recruitment in Aspergillus fumigatus Phagosomes via Targeting Dectin-1/Syk Kinase Signaling
Irene Kyrmizi,Mark S. Gresnigt,Tonia Akoumianaki,George Samonis,Prodromos Sidiropoulos,Dimitrios T. Boumpas,Dimitrios T. Boumpas,Mihai G. Netea,Frank L. van de Veerdonk,Dimitrios P. Kontoyiannis,Georgios Chamilos,Georgios Chamilos +11 more
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TLDR
It is 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, which was induced by surface exposure of immunostimulatory β-glucans and was mediated by activation of the Dectin-1 receptor.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.read more
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Immunity to Fungal Infections
TL;DR: The nature and function of the immune response to fungi is an exciting challenge that might set the stage for new approaches to the treatment of fungal diseases, from immunotherapy to vaccines.
Journal ArticleDOI
Aspergillus fumigatus and Aspergillosis in 2019
TL;DR: The emergence of new concepts, such as nutritional immunity and the integration and rewiring of multiple fungal metabolic activities occurring during lung invasion, has helped to redefine the opportunistic pathogenesis of A. fumigatus.
Journal ArticleDOI
Aspergillus Fumigatus Morphology and Dynamic Host Interactions
TL;DR: This Review describes how A. fumigatus adapts to environmental change, the mechanisms of host defence, and the current knowledge of the interplay between the host immune response and the fungus.
Journal ArticleDOI
IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans
Antonella De Luca,Sanne P. Smeekens,Andrea Casagrande,Rossana G. Iannitti,Kara L. Conway,Mark S. Gresnigt,Jakob Begun,Theo S. Plantinga,Leo A. B. Joosten,Jos W. M. van der Meer,Georgios Chamilos,Mihai G. Netea,Ramnik J. Xavier,Ramnik J. Xavier,Charles A. Dinarello,Charles A. Dinarello,Luigina Romani,Frank L. van de Veerdonk,Frank L. van de Veerdonk +18 more
TL;DR: Inflammation in CGD is due to IL-1–dependent mechanisms, such as decreased autophagy and increased inflammasome activation, which are linked pathological conditions inCGD that can be restored byIL-1 receptor blockade.
Journal ArticleDOI
LC3-Associated Phagocytosis and Inflammation.
TL;DR: A detailed review of LAP and its known roles in the immune response is provided and further speculation on the putative mechanisms by which LAP may regulate immune function is provided, perhaps through the metabolic reprogramming and polarization of macrophages.
References
More filters
Journal ArticleDOI
The role of autophagy during the early neonatal starvation period
Akiko Kuma,Masahiko Hatano,Makoto Matsui,Makoto Matsui,Akitsugu Yamamoto,Haruaki Nakaya,Tamotsu Yoshimori,Yoshinori Ohsumi,Takeshi Tokuhisa,Noboru Mizushima,Noboru Mizushima,Noboru Mizushima +11 more
TL;DR: The results suggest that the production of amino acids by autophagic degradation of ‘self’ proteins, which allows for the maintenance of energy homeostasis, is important for survival during neonatal starvation.
Journal ArticleDOI
Quantifying cellular oxidative stress by dichlorofluorescein assay using microplate reader.
Hong Wang,James A. Joseph +1 more
Journal ArticleDOI
Immunity to fungal infections
TL;DR: Research in this field is entering an exciting period of transition from studying the molecular and cellular bases of fungal virulence to determining the cellular and molecular mechanisms that maintain immune homeostasis with fungi.
Journal ArticleDOI
Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis
Miguel A. Sanjuan,Christopher P. Dillon,Stephen W.G. Tait,Simon Moshiach,Frank C. Dorsey,Samuel Connell,Masaaki Komatsu,Keiji Tanaka,John L. Cleveland,Sebo Withoff,Douglas R. Green +10 more
TL;DR: It is shown that a particle that engages TLRs on a murine macrophage while it is phagocytosed triggers the autophagosome marker LC3 to be rapidly recruited to the phagosome in a manner that depends on theAutophagy pathway proteins ATG5 and ATG7; this process is preceded by recruitment of beclin 1 and phosphoinositide-3-OH kinase activity.
Journal ArticleDOI
Dectin-1 Mediates the Biological Effects of β-Glucans
Gordon D. Brown,Jurgen Herre,David L. Williams,Janet A. Willment,Andrew S J Marshall,Siamon Gordon +5 more
TL;DR: It is shown that Dectin-1 mediates the production of TNF-α in response to zymosan and live fungal pathogens, an activity that occurs at the cell surface and requires the cytoplasmic tail and immunoreceptor tyrosine activation motif of Dect in addition to Toll-like receptor (TLR)-2 and Myd88.