Human dendritic cell subsets display distinct interactions with the pathogenic mould Aspergillus fumigatus

Lother, Jasmin; Breitschopf, Tanja; Krappmann, Sven; Morton, Oliver; Bouzani, Maria; Kurzai, Oliver; Gunzer, Matthias; Hasenberg, Mike; Einsele, Hermann; Loeffler, Juergen

doi:10.1016/j.ijmm.2014.08.009

Cited by 32 publications

(26 citation statements)

References 45 publications

(65 reference statements)

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“…To preserve fungal morphotypes during coculture experiments, conidia and germ tubes were inactivated with 100% ethanol (Sigma) for 30 min, washed five times with sterile water, and stored in RPMI at −20°C. For time-lapse microscopy red fluorescent A. fumigatus conidia and germ tubes were generated as described before ( 9 ).…”

Section: Methodsmentioning

confidence: 99%

“…Peripheral blood mononuclear cells were isolated from leukocyte concentrates from healthy human donors (Institute of Transfusion Medicine, University Hospital of Wuerzburg) by Ficoll (Biochrome) density centrifugation. After positive magnetic selection of CD14 + cells (CD14 MicroBeads, Miltenyi Biotec), monocytes were cultured for 5 days in RPMI 1640 medium supplemented with 10% fetal calf serum (FCS) (Sigma), rGM-CSF (100 ng/ml, Bayer), and rIL4 (10 ng/ml, Miltenyi Biotec) ( 9 ).…”

Section: Methodsmentioning

confidence: 99%

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Human and Murine Innate Immune Cell Populations Display Common and Distinct Response Patterns during Their In Vitro Interaction with the Pathogenic Mold Aspergillus fumigatus

et al. 2017

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Aspergillus fumigatus is the main cause of invasive fungal infections occurring almost exclusively in immunocompromised patients. An improved understanding of the initial innate immune response is key to the development of better diagnostic tools and new treatment options. Mice are commonly used to study immune defense mechanisms during the infection of the mammalian host with A. fumigatus. However, little is known about functional differences between the human and murine immune response against this fungal pathogen. Thus, we performed a comparative functional analysis of human and murine dendritic cells (DCs), macrophages, and polymorphonuclear cells (PMNs) using standardized and reproducible working conditions, laboratory protocols, and readout assays. A. fumigatus did not provoke identical responses in murine and human immune cells but rather initiated relatively specific responses. While human DCs showed a significantly stronger upregulation of their maturation markers and major histocompatibility complex molecules and phagocytosed A. fumigatus more efficiently compared to their murine counterparts, murine PMNs and macrophages exhibited a significantly stronger release of reactive oxygen species after exposure to A. fumigatus. For all studied cell types, human and murine samples differed in their cytokine response to conidia or germ tubes of A. fumigatus. Furthermore, Dectin-1 showed inverse expression patterns on human and murine DCs after fungal stimulation. These specific differences should be carefully considered and highlight potential limitations in the transferability of murine host–pathogen interaction studies.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Human and Murine Innate Immune Cell Populations Display Common and Distinct Response Patterns during Their In Vitro Interaction with the Pathogenic Mold Aspergillus fumigatus

et al. 2017

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“…The clinical isolate of A. fumigatus ATCC46645 strain ( Hearn and Mackenzie, 1980 ) was routinely used. Fluorescent A. fumigatus strain Afu-TdTomato ( Lother et al, 2014 ) generated from ATCC46645 (kindly provided by Dr. Sven Krappmann) was used to determine fungal developmental stages inside lung tissue. All the fungal strains were cultivated on defined minimal medium ( Amich et al, 2013 ) under standard culture conditions and handled according to German laboratory safety guidelines.…”

Section: Methodsmentioning

confidence: 99%

Dynamic Immune Cell Recruitment After Murine Pulmonary Aspergillus fumigatus Infection under Different Immunosuppressive Regimens

et al. 2016

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Humans are continuously exposed to airborne spores of the saprophytic fungus Aspergillus fumigatus. However, in healthy individuals pulmonary host defense mechanisms efficiently eliminate the fungus. In contrast, A. fumigatus causes devastating infections in immunocompromised patients. Host immune responses against A. fumigatus lung infections in immunocompromised conditions have remained largely elusive. Given the dynamic changes in immune cell subsets within tissues upon immunosuppressive therapy, we dissected the spatiotemporal pulmonary immune response after A. fumigatus infection to reveal basic immunological events that fail to effectively control invasive fungal disease. In different immunocompromised murine models, myeloid, notably neutrophils, and macrophages, but not lymphoid cells were strongly recruited to the lungs upon infection. Other myeloid cells, particularly dendritic cells and monocytes, were only recruited to lungs of corticosteroid treated mice, which developed a strong pulmonary inflammation after infection. Lymphoid cells, particularly CD4+ or CD8+ T-cells and NK cells were highly reduced upon immunosuppression and not recruited after A. fumigatus infection. Moreover, adoptive CD11b+ myeloid cell transfer rescued cyclophosphamide immunosuppressed mice from lethal A. fumigatus infection but not cortisone and cyclophosphamide immunosuppressed mice. Our findings illustrate that CD11b+ myeloid cells are critical for anti-A. fumigatus defense under cyclophosphamide immunosuppressed conditions.

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“…A. fumigatus ATCC 46645, the GFP-expressing strain AfS148 (58), the melanin-free pksP mutant (53), and the mitochondrial GFP reporter strain AfS35 pJW103 (49) were maintained on malt extract (Sigma-Aldrich) agar plates supplemented with 2% (w/v) agar for 5 days at 37°C. When appropriate, A. fumigatus ATCC 46645 and the overexpression strains A. fumigatus Afazuro, AfcathG, and AfRBP7 were cultivated on Aspergillus Minimal Medium (AMM) for 3 days at 37°C, as described (59).…”

Section: Methodsmentioning

confidence: 99%

Human neutrophils produce antifungal extracellular vesicles againstAspergillus fumigatus

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Belyaev

Dasari

et al. 2019

Preprint

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AbstractPolymorphonuclear granulocytes (PMNs) are indispensable for controlling life-threatening fungal infections. In addition to various effector mechanisms, PMNs also produce extracellular vesicles (EVs). Their contribution to antifungal defense has remained unexplored. We reveal that the clinically important human pathogenic fungus Aspergillus fumigatus triggers PMNs to release a distinct set of antifungal EVs (afEVs). Proteome analyses indicated that afEVs are enriched in antimicrobial proteins. The cargo and release kinetics of EVs are modulated by the fungal strain confronted. Tracking of afEVs indicated that they associated with fungal cells and even entered fungal hyphae, resulting in alterations in the morphology of the fungal cell wall and dose-dependent antifungal effects. Two human proteins enriched in afEVs, cathepsin G and azurocidin, were heterologously expressed in fungal hyphae, which led to reduced fungal growth relative to a control retinol binding protein 7 producing strain. In conclusion, the production of afEVs by PMNs offers an intriguing, previously overlooked mechanism of antifungal defense against A. fumigatus.ImportanceInvasive fungal infections caused by the mold Aspergillus fumigatus are a growing concern in the clinic due to the increasing use of immunosuppressive therapies and increasing antifungal drug resistance. These infections result in high mortality as treatment and diagnostic options remain limited. In healthy individuals, neutrophilic granulocytes are critical for elimination of A. fumigatus from the host; however, the exact extracellular mechanism of neutrophil-mediated antifungal activity remains unresolved. Here, we present a mode of antifungal defense employed by human neutrophils against A. fumigatus not previously described. We find that extracellular vesicles produced by neutrophils in response to A. fumigatus infection are able to associate with the fungus, limit growth, and elicit cell damage by delivering antifungal cargo. In the end, antifungal extracellular vesicle biology provides a significant step forward in our understanding of A. fumigatus host pathogenesis and opens up novel diagnostic and therapeutic possibilities.

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Human dendritic cell subsets display distinct interactions with the pathogenic mould Aspergillus fumigatus

Cited by 32 publications

References 45 publications

Human and Murine Innate Immune Cell Populations Display Common and Distinct Response Patterns during Their In Vitro Interaction with the Pathogenic Mold Aspergillus fumigatus

Human and Murine Innate Immune Cell Populations Display Common and Distinct Response Patterns during Their In Vitro Interaction with the Pathogenic Mold Aspergillus fumigatus

Dynamic Immune Cell Recruitment After Murine Pulmonary Aspergillus fumigatus Infection under Different Immunosuppressive Regimens

Human neutrophils produce antifungal extracellular vesicles againstAspergillus fumigatus

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