Dectin-1/CARD9-induction of the TFEB and TFE3 gene network is dispensable for phagocyte anti-Aspergillus activity in the lung.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE233353 | GEO | 2023/08/07
REPOSITORIES: GEO
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Project description:Aspergillus fumigatus is an important human fungal pathogen and its conidia are constantly inhaled by humans. In immunocompromised individuals, conidia can grow out as hyphae that damage lung epithelium. The resulting invasive aspergillosis is associated with devastating mortality rates. Since infection is a race between the innate immune system and the outgrowth of A. fumigatus conidia, we use dynamic optimization to obtain insight into the recruitment and depletion of alveolar macrophages and neutrophils. We illustrate by modeling the active, but so far neglected, major role of alveolar epithelial cells in phagocytosis and cytokine release as well as the importance of fungal growth states for virulence.
Hence, we discovered that germination speed is a key virulence trait of fungal pathogens due to the vulnerability of conidia against host defense. We proved this by linking measured germination kinetics of four Aspergillus spp. with their cytotoxicity against epithelial cells in silico and in vitro.Furthermore, we could reveal by modeling and ex vivo measurements, that epithelial cells are not only important phagocytes to clear conidia, but also potent mediators of cytokine release.
In conclusion, our findings illustrate an underestimated role of epithelial cells in invasive aspergillosis. Further, our model affirms the importance of neutrophils and underlines that the role of macrophages in invasive aspergillosis remains elusive.
We expect that our model will contribute to improvement of treatment protocols by focusing on
the critical components of immune response to fungi but also fungal virulence.
2021-11-24 | MODEL2105110001 | BioModels
Project description:Aspergillus fumigatus is an important human pathogen and a leading fungal killer. This study aimed to determine the small RNA repertoire of A. fumigatus in conidia and mycelium grown for 24 or 48 hours in liquid culture.
2023-02-14 | GSE223619 | GEO
Project description:Response of A549 cells treated with Aspergillus fumigatus wild type germinating conidia (WT_GC) or PrtT protease deficient mutant conidia (PrtT-GC) or inert acrylic 2-4 micron beads (Beads) for 8h Aspergillus fumigatus is the most commonly encountered mold pathogen of humans, predominantly infecting the respiratory system. Colonization and penetration of the lung alveolar epithelium is a key but poorly understood step in the infection process. This study focused on identifying the transcriptional and cell-signaling responses activated in A549 alveolar carcinoma cells incubated in the presence of A. fumigatus wild-type and ÎPrtT protease-deficient germinating conidia and culture filtrates (CF). Microarray analysis of exposed A549 cells identified distinct classes of genes whose expression is altered in the presence of germinating conidia and CF and suggested the involvement of both NFkB and MAPK signaling pathways in mediating the cellular response. Phosphoprotein analysis of A549 cells confirmed that JNK and ERK1/2 are phosphorylated in response to CF treatment in a protease-dependent manner. Inhibition of JNK or ERK1/2 kinase activity substantially decreased CF-induced cell damage, including cell peeling, actin-cytoskeleton damage, and reduction in metabolic activity and necrotic death. These results suggest that inhibition of MAPK-mediated host responses to treatment with A. fumigatus CF decreases cellular damage, a finding with possible clinical implications. 2 independent controls (uninfected A549 cells) as ctrl3_1-2, 2 independent treatments of A549 cells with wild-type A. fumigatus germinating conidia (WT_GC_1-2 ) , 2 independent treatments of A549 cells with inert acrylic beads (Beads 1-2), 3 independent treatments of A549 cells with A. fumigatus prtT mutant germinating conidia (PrtT-GC_1-3).
2010-10-29 | E-GEOD-24984 | biostudies-arrayexpress
Project description:DCs play a central role for the immune response against the mold Aspergillus fumigatus. Hypoxic microenvironments occur during infection with A. fumigatus. Hypoxia and signaling via hypoxia inducible factor 1α may modulate the response of DCs; however, the role in fungal infections is unclear. We used microarrays to determine the influence of hypoxia and HIF-1α signaling on the immune response of human DCs towards A. fumigatus.
2015-11-01 | GSE60729 | GEO
Project description:Inhalation of conidia of the opportunistic mold Aspergillus fumigatus by immunocompromised hosts can lead to invasive pulmonary disease. Inhaled conidia that escape immune defenses germinate to form filamentous hyphae that invade lung tissues. Conidiation rarely occurs during invasive infection of the human host, allowing the bulk of fungal energy to be directed towards vegetative growth. We hypothesized that forced induction of conidiation during infection can suppress A. fumigatus vegetative growth, impairing the ability of this organism to cause disease. To study the effects of conidiation pathway dysregulation on A. fumigatus virulence, a key transcriptional regulator of conidiation (brlA) was expressed under the control of a doxycycline-inducible promoter. Time- and dose-dependent brlA overexpression was observed in response to doxycycline both in vitro and in vivo. Exposure of the inducible brlA overexpression strain to low doses of doxycycline under vegetative growth conditions in vitro induced conidiation, while high doses arrested growth. Overexpression of brlA attenuated A. fumigatus virulence in both an invertebrate and mouse model of invasive aspergillosis. RNA sequencing studies and phenotypic analysis revealed that brlA-overexpression results in altered cell signaling, amino acid and carbohydrate metabolism, including a marked up-regulation of trehalose biosynthesis and a downregulation in the biosynthesis of the polysaccharide virulence factor galactosaminogalactan. This proof-of-concept study demonstrates that activation of the conidiation pathway in A. fumigatus can reduce virulence and suggests that brlA-inducing small molecules may hold promise as a new class of therapeutics for A. fumigatus infection.
2020-01-15 | GSE143601 | GEO
Project description:Neutrophil-derived extracellular vesicles have regained scientific interest as potent ‘wireless’ modulators with pleiotropic effects on the immune system. A few studies have addressed their role in the context of microbial pathogenesis showing their bacteriostatic effects against Staphylococcus aureus in vitro and their potential as diagnostic markers in the onset of bacterimic sepsis in vivo. Here, we provided first insights into the vesicle release driven by the clinically relevant pathogenic fungus Aspergillus fumigatus that causes invasive infections in immunocompromised individuals worldwide often with a lethal outcome. Neutrophils, stimulated with fungal spores, potently produced vesicles that we refer as anti-fungal extracellular vesicles (afEVs). We revealed that the conidial surface pigment of A. fumigatus dihydroxynaphthalene (DHN) melanin - a well known fungal virulence factor - is a key ‘switch-on/off’ governing vesicle production. We profiled the kinetics of afEV formation and showed that DHN-melanin interferes with the vesicle number, vesicle surface maturation markers such as CD11b, CD63 and CD177 and governs the enrichment of distinct afEV subpopulations unrelated to apoptosis. Simultaneously we tracked down the fate of neutrophils during afEV formation and observed mulivesicular body formation that led to active export of CD11b, CD63 and CD177 by shedding from the surface of neutrophils onto the surface afEVs. By dissecting the proteome cargo of afEVs produced against wild-type and melanin-free conidia we verified that DHN-melanin also manipulates the type of cargo neutrophils accumulate in the vesicles upon confronting conidia with different cell wall integrity. afEVs contained higher amounts of antimicrobial peptides than spontaneously released EVs from uninfected neutrophils. Last but not least afEVs exhibit fungistatic effects and also modulate cell wall morphogenesis of hyphae.
2019-05-17 | PXD005994 | Pride
Project description:Serum amyloid P component (SAP; APCS gene, also known as Pentraxin 2, PTX2), is a component of the humoral arm of innate immunity involved in resistance to bacterial infection and regulation of tissue remodeling. The present study was designed to investigate the role of SAP/PTX2 in antifungal resistance. SAP-deficient Apcs-/- mice showed a dramatic increase in susceptibility to A. fumigatus infection. The defective anti-fungal resistance of gene targeted mice was rescued by in vitro opsonization of A. fumigatus conidia and in vivo administration of murine SAP. Mouse and human SAP bound conidia, activated the complement cascade and increased phagocytosis by mouse and human neutrophils. Defective resistance of Apcs-/- SAP-deficient mice was associated with defective in vivo recruitment of neutrophils and phagocytosis in the lungs. The opsonic activity of SAP was dependent on the classical pathway of complement activation. In immunosuppressed mice, SAP administration protected hosts against A. fumigatus infection and death. In the context of a study of hematopoietic stem-cell transplantation, genetic variation in the human APCS gene was associated with susceptibility to invasive pulmonary aspergillosis. Thus, SAP is a fluid phase pattern recognition molecule essential for resistance against A. fumigatus. The results reported here also suggest that SAP has therapeutic potential against an infectious agent which represents a formidable clinical challenge.
2021-04-20 | GSE163533 | GEO
Project description:Response of A549 cells treated with Aspergillus fumigatus germinating conidia (WT-GC) or culture filtrate (WT-CF) for 8h Aspergillus fumigatus is the most commonly encountered mold pathogen of humans, predominantly infecting the respiratory system. Colonization and penetration of the lung alveolar epithelium is a key but poorly understood step in the infection process. This study focused on identifying the transcriptional and cell-signaling responses activated in A549 alveolar carcinoma cells incubated in the presence of A. fumigatus wild-type and ÎPrtT protease-deficient germinating conidia and culture filtrates (CF). Microarray analysis of exposed A549 cells identified distinct classes of genes whose expression is altered in the presence of germinating conidia and CF and suggested the involvement of both NFkB and MAPK signaling pathways in mediating the cellular response. Phosphoprotein analysis of A549 cells confirmed that JNK and ERK1/2 are phosphorylated in response to CF treatment in a protease-dependent manner. Inhibition of JNK or ERK1/2 kinase activity substantially decreased CF-induced cell damage, including cell peeling, actin-cytoskeleton damage, and reduction in metabolic activity and necrotic death. These results suggest that inhibition of MAPK-mediated host responses to treatment with A. fumigatus CF decreases cellular damage, a finding with possible clinical implications. 3 independent controls (uninfected A549 cells) as ctrl2_1-3, 2 independent treatments of A549 cells with wild-type A. fumigatus culture filtrates (WT-CF2_1-2) and 2 independent treatments of A549 cells with wild-type A. fumigatus germinating conidia (WT-GC_2-3).
2010-10-29 | E-GEOD-24983 | biostudies-arrayexpress
Project description:Fungal spores and hyphal fragments are major contributors to the allergic response in the human lung. In this study, using a trypsin-shaving-proteomics approach, we identified the surface-exposed and secreted/shed proteins of Aspergillus fumigatus conidia and investigated the dynamics of the surface proteome under different conditions, including temperature variation and germination. We find that the surface proteome of resting A. fumigatus conidia is quite dynamic, as evidenced by drastically different surface proteomes under different growth conditions. We further investigated two observed A. fumigatus surface proteins, ScwA and CweA; ScwA is specific to the Aspergillus genus and only expressed on conidia grown at higher temperatures, whereas CweA is found throughout the Aspergillus and Penicillium genera. We extended our analysis of the surface proteome of A. fumigatus to other allergy-inducing pathogens; Alternaria alternata, Penicillium rubens, and Cladosporium herbarum, and performed comparative proteomics on resting and swollen conidia, as well as secreted proteins from germinating conidia. In this dataset, we detected 125 protein orthologs in the extracellular region of all four organisms, and 42 nonorthologous proteins produced by A. fumigatus, which may be useful in the development of future diagnostics. This study highlights the dynamic nature of the conidial surface and implicates growth conditions in the antigenicity of fungal conidia.
2020-01-24 | PXD017067 | Pride
Project description:Fungal infections remain a tremendous source of global morbidity and mortality, with more than 1 billion individuals affected by fungal infections each year. Invasive infections are particularly dangerous and kill numbers on par with tuberculosis or malaria. Aspergillus fumigatus is a major source of invasive fungal infections in humans, and is particularly dangerous to the immunocompromised. In many cases, research into invasive fungal infections is limited by a lack of model systems. In this study we hypothesized that cultured, differentiated human PLB-985 neutrophil-like cells could serve as model system to study the host-pathogenesis of A. fumigatus. We tested this hypothesis by defining the phagocytosis and intracellular trafficking of A. fumigatus conidia by PLB-985 cells, the production of neutrophil extracellular traps, and by characterizing extracellular vesicles produced in response to infection. As part of this analysis, we performed a detailed LC-MS/MS-based proteomic comparison of extracellular vesicles isolated by two different methods, centrifugation-based isolation or size-exclusion chromatography. We find numerous similarities between primary neutrophils and PLB-985 cells that suggest differentiated PLB-985 cells can serve as a tractable in vitro model system for further study of many aspects of A. fumigatus pathogenesis.
2021-07-30 | PXD027032 | Pride