Phosphatidylinositol 3-Kinase (PI3K) Orchestrates Aspergillus fumigatus-Induced Eosinophil Activation Independently of Canonical Toll-Like Receptor (TLR)/C-Type-Lectin Receptor (CLR) Signaling

Dietschmann, Axel; Schruefer, Sebastian; Westermann, Stefanie; Henkel, Fiona; Castiglione, Kirstin; Willebrand, Ralf; Adam, Jasmin; Ruland, Jürgen; Lang, Roland; Sheppard, Donald C.; Bieren, Julia Esser‐von; Radtke, Daniel; Krappmann, Sven; Voehringer, David

doi:10.1128/mbio.01239-22

Cited by 6 publications

(3 citation statements)

References 80 publications

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“…We found that E_C3/E_C4 clusters could recruit TAM_GPNMB through the ligand‒receptor pairs CCL3/CCL4-CCR3 (Fig. 7A ) [ 55 ]. Moreover, with the expression of TGF-β family genes, including TGFB1, TGFB3 and HBEGF, these two subclusters could induce the involvement of TAM_GPNMB in extracellular matrix remodelling, thereby promoting the migration of KCs (Fig.…”

Section: Resultsmentioning

confidence: 99%

Multiomics integration-based immunological characterizations of adamantinomatous craniopharyngioma in relation to keratinization

Xu,

Wu,

et al. 2024

Cell Death Dis

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Although adamantinomatous craniopharyngioma (ACP) is a tumour with low histological malignancy, there are very few therapeutic options other than surgery. ACP has high histological complexity, and the unique features of the immunological microenvironment within ACP remain elusive. Further elucidation of the tumour microenvironment is particularly important to expand our knowledge of potential therapeutic targets. Here, we performed integrative analysis of 58,081 nuclei through single-nucleus RNA sequencing and spatial transcriptomics on ACP specimens to characterize the features and intercellular network within the microenvironment. The ACP environment is highly immunosuppressive with low levels of T-cell infiltration/cytotoxicity. Moreover, tumour-associated macrophages (TAMs), which originate from distinct sources, highly infiltrate the microenvironment. Using spatial transcriptomic data, we observed one kind of non-microglial derived TAM that highly expressed GPNMB close to the terminally differentiated epithelial cell characterized by RHCG, and this colocalization was verified by asmFISH. We also found the positive correlation of infiltration between these two cell types in datasets with larger cohort. According to intercellular communication analysis, we report a regulatory network that could facilitate the keratinization of RHCG+ epithelial cells, eventually causing tumour progression. Our findings provide a comprehensive analysis of the ACP immune microenvironment and reveal a potential therapeutic strategy base on interfering with these two types of cells.

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Section: Resultsmentioning

confidence: 99%

Multiomics integration-based immunological characterizations of adamantinomatous craniopharyngioma in relation to keratinization

Xu,

Wu,

et al. 2024

Cell Death Dis

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“…Surprisingly, expression of L-selectin (CD62L), a neutrophil marker of adhesion to endothelial cells and migration ( 53 ), was increased in response to supernatants of infected VECs and lower in the presence of anti-candidalysin nanobodies. CD62L is expected to be inversely regulated with CD11b during granulocyte activation in vitro ( 54 – 56 ), since CD62L is rapidly shed during activation ( 53 ). It is, therefore, difficult to determine how the increased CD62L surface expression, which was reduced by the nanobodies, reflects neutrophil activation state.…”

Section: Discussionmentioning

confidence: 99%

“…To prevent unspecific staining, neutrophils were pre-incubated with Fc-Block Human TruStain FcX (BioLegend) before adding a mix of fluorophore-linked antibodies against the following activation status indicating surface molecules: CD11b-BV421 (ICR44), CD15-APC-Fire750 (W6D3), CD16-PerCP-Cy5.5 (3G8), CD35-FITC (E11), CD62L-AlexaFluor647 (DREG-56), CD66b-PE (G10F5), and CD182-PE-Cy7 (5E8, all from BioLegend). Activation markers were selected based on previous observations of granulocyte responses to fungal pathogens or associated stimuli ( 52 , 54 , 57 ). Fixable Viability Dye eFluor506 (Invitrogen) was used to exclude dead cells.…”

Section: Methodsmentioning

confidence: 99%

Nanobody-mediated neutralization of candidalysin prevents epithelial damage and inflammatory responses that drive vulvovaginal candidiasis pathogenesis

Valentine,

Rudolph,

Dietschmann

et al. 2024

mBio

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Worldwide, vaginal infections caused by Candida albicans (VVC) annually affect millions of women, with symptoms significantly impacting quality of life. Current treatments are based on anti-fungals and probiotics that target the fungus. However, in some cases, infections are recurrent, called recurrent VVC, which often fails to respond to treatment. Vaginal mucosal tissue damage caused by the C. albicans peptide toxin candidalysin is a key driver in the induction of hyperinflammatory responses that fail to clear the infection and contribute to immunopathology and disease severity. In this pre-clinical evaluation, we show that nanobody-mediated candidalysin neutralization reduces tissue damage and thereby limits inflammation. Implementation of candidalysin-neutralizing nanobodies may prove an attractive strategy to alleviate symptoms in complicated VVC cases.

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Fungal Enzyme Inhibitors: Potent Repository of Lead Compounds to Curb Cancer

Gambhir,

Kapoor

2024

Fungi Bioactive Metabolites

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Phosphatidylinositol 3-Kinase (PI3K) Orchestrates Aspergillus fumigatus-Induced Eosinophil Activation Independently of Canonical Toll-Like Receptor (TLR)/C-Type-Lectin Receptor (CLR) Signaling

Abstract: 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.

Cited by 6 publications

References 80 publications

Multiomics integration-based immunological characterizations of adamantinomatous craniopharyngioma in relation to keratinization

Multiomics integration-based immunological characterizations of adamantinomatous craniopharyngioma in relation to keratinization

Nanobody-mediated neutralization of candidalysin prevents epithelial damage and inflammatory responses that drive vulvovaginal candidiasis pathogenesis

Fungal Enzyme Inhibitors: Potent Repository of Lead Compounds to Curb Cancer

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