PuSH - Publication Server of Helmholtz Zentrum München: Phosphatidylinositol 3-kinase (PI3K) orchestrates <em>Aspergillus fumigatus</em>-induced eosinophil activation independently of canonical toll-like receptor (TLR)/C-type-lectin receptor (CLR) signaling.

Navigation

Home

Deutsch

Research

Advanced Search

Browse by ...

... Journal

... Publication Type

... Research Data

... Publication Year

Publication overview

Support & Contact

Contact persons

Help

Data protection

Dietschmann, A.* ; Schruefer, S.* ; Westermann, S.* ; Henkel, F. ; Castiglione, K.* ; Willebrand, R.* ; Adam, J.* ; Ruland, J.* ; Lang, R.* ; Sheppard, D.C.* ; Esser-von Bieren, J. ; Radtke, D.* ; Krappmann, S.* ; Voehringer, D.*

Phosphatidylinositol 3-kinase (PI3K) orchestrates Aspergillus fumigatus-induced eosinophil activation independently of canonical toll-like receptor (TLR)/C-type-lectin receptor (CLR) signaling.

mBio 13:e0123922 (2022)

Publ. Version/Full Text

Research data

DOI

PMC

	Open Access Gold

Abstract
Metrics
Extra information

Eosinophilia is associated with various persisting inflammatory diseases and often coincides with chronic fungal infections or fungal allergy as in the case of allergic bronchopulmonary aspergillosis (ABPA). Here, we show that intranasal administration of live Aspergillus fumigatus conidia causes fatal lung damage in eosinophilic interleukin-5 (IL-5)-transgenic mice. To further investigate the activation of eosinophils by A. fumigatus, we established a coculture system of mouse bone marrow-derived eosinophils (BMDE) with different A. fumigatus morphotypes and analyzed the secretion of cytokines, chemokines, and eicosanoids. A. fumigatus-stimulated BMDE upregulated expression of CD11b and downregulated CD62L and CCR3. They further secreted several proinflammatory mediators, including IL-4, IL-13, IL-18, macrophage inflammatory protein-1α (MIP-1α)/CC chemokine ligand 3 (CCL3), MIP-1β/CCL4, and thromboxane. This effect required direct interaction and adherence between eosinophils and A. fumigatus, as A. fumigatus culture supernatants or A. fumigatus mutant strains with impaired adhesion elicited a rather poor eosinophil response. Unexpectedly, canonical Toll-like receptor (TLR) or C-type-lectin receptor (CLR) signaling was largely dispensable, as the absence of MYD88, TRIF, or caspase recruitment domain-containing protein 9 (CARD9) resulted in only minor alterations. However, transcriptome analysis indicated a role for the PI3K-AKT-mTOR pathway in A. fumigatus-induced eosinophil activation. Correspondingly, we could show that phosphatidylinositol 3-kinase (PI3K) inhibitors successfully prevent A. fumigatus-induced eosinophil activation. The PI3K pathway in eosinophils may therefore serve as a potential drug target to interfere with undesired eosinophil activation in fungus-elicited eosinophilic disorders. IMPORTANCE Allergic bronchopulmonary aspergillosis (ABPA) is caused by the fungus Aspergillus fumigatus, afflicts about five million patients globally, and is still a noncurable disease. ABPA is associated with pronounced lung eosinophilia. Activated eosinophils enhance the inflammatory response not only by degranulation of toxic proteins but also by secretion of small effector molecules. Receptors and signaling pathways involved in activation of eosinophils by A. fumigatus are currently unknown. Here, we show that A. fumigatus-elicited activation of eosinophils requires direct cell-cell contact and results in modulation of cell surface markers and rapid secretion of cytokines, chemokines, and lipid mediators. Unexpectedly, this activation occurred independently of canonical Toll-like receptor or C-type lectin receptor signaling. However, transcriptome analysis indicated a role for the PI3K-AKT-mTOR pathway, and PI3K inhibitors successfully prevented A. fumigatus-induced eosinophil activation. The PI3K pathway may therefore serve as a potential drug target to interfere with undesired eosinophil activation in fungus-elicited eosinophilic disorders.

Altmetric

Additional Metrics?

[➜Log in]

Edit extra informations Login

Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Aspergillus Fumigatus ; C-type Lectin Receptor ; Toll-like Receptor ; Eosinophils ; Phosphatidylinositol-3-kinase

ISSN (print) / ISBN 2150-7511

e-ISSN 2150-7511

Journal mBio

Quellenangaben Volume: 13, Issue: 4, Article Number: e0123922

Publisher American Society for Microbiology (ASM)

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute for Allergy Research (IAF)

Grants Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg
Deutsche Forschungsgemeinschaft
Friedrich-Alexander-Universität Erlangen-Nürnberg
Interdisciplinary Center for Clinical Studies