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Healthy peripheral neutrophils total RNA-Seq: Serum Amyloid P component is an essential element of resistance against Aspergillus fumigatus

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE163533 | GEO | 2021/04/20

REPOSITORIES: GEO

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Ewald2021 - Innate immune response during invasive aspergillosis by dynamic optimization

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

Dectin-1/CARD9-induction of the TFEB and TFE3 gene network is dispensable for phagocyte anti-Aspergillus activity in the lung.

Project description:Neutrophils play a crucial role in immunity against Aspergillus fumigatus, the most common etiologic agent of mold pneumonia worldwide. Phagocytes rapidly engulf A. fumigatus conidia in the lung to prevent germination and tissue damage. Phagosome maturation, including fusion with the lysosome, is a critical process in killing conidia but if this regulated at the transcriptional level remains unknown. To investigate the transcriptional response in neutrophils to fungal engagement, we compared the transcriptomes of lung neutrophils that were either bystanders or engaged with fungal cells.

2023-08-07 | GSE233353 | GEO

The responses of the pulmonary pathogen Aspergillus fumigatus to the neutrophil derived oxidant N- chlorotaurine

Project description:Aspergillus fumigatus is a pulmonary pathogen to individuals who are immunocompromised (e.g. mylosuppression) and those who display defects in immune equilibrium, commonly observed in the Cystic fibrosis lung and presents itself in the form as allergic bronchopulmonary aspergillosis.32 In the latter disease A. fumigatus airborne conidia penetrate the lower airways, germinate and and grow within in thick tenacious CF mucus. A. fumigatus CF colonized individuals can become sensitized to A. fumigatus secreted allergens and eventually develop a type 2 hypersensitivity reaction to AF allergens, toxins and proteases which are readily replenished into the mucus which can directly cause cell damage and peeling at the bronco – epithelium interface. A. fumigatus also induces invasive disease which carries up to 90% mortality. The effect of neutrophil oxidant NCT on A. fumigatus was determined as neutrophils are the first line of cellular defense against A. fumigatus.

2018-12-19 | PXD009853 | Pride

Human p11-mediated re-direction of phagosomes to the recycling endosome-expulsion pathway induced by fungal pathogen

Project description:Aspergillus fumigatus invades pulmonary epithelial cells by induced phagocytosis, and survives for some time in phagosomes. Although dihydroxynaphthalene melanin on fungal conidia has been intensively investigated for its role in inhibiting phagosome maturation, a proportion of melanin-lacking mutant conidia still escaped killing by phagosomes, implying that additional mechanisms must be in place. Here, we identified the fungal surface-exposed heat shock protein HscA as an effector protein that binds the human p11 protein. A. fumigatus induces and increases the amount of p11 and anchors p11 and Annexin A2 to phagosomes and phagocytic cups, the latter facilitates phagocytosis of conidia by epithelial cells. We identified a SNP in the in the non-coding region of the human p11 gene resulting in heightened susceptibility for invasive aspergillosis in hematopoietic stem-cell transplant recipients. This finding can help for stratification of donors for hematopoietic stem cell transplantation. On phagosomes, HscA triggers an increase of p11 on the phagosomal membrane, which prevents directing the phagosome to the degradative pathway by re-directing the p11-positive phagosome to the recycling endosomal pathway. Therefore, a surface-located heat shock protein enables fungal conidia to escape phagolysosome killing.

2023-03-13 | PXD030501 | Pride

Aspergillus fumigatus melanin manipulates the cargo and kinetics of neutrophil-derived extracellular vesicles

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

The In Vitro Interaction of Aspergillus fumigatus and Human immature Dendritic Cells

Project description:Dendritic cells (DC) play an important role in host immunity by acting as a bridge between the innate and adaptive immune systems. They are antigen presenting cells that obtain microbial antigens by direct phagocytosis of the microbe or by cross presentation of antigens taken up from the surrounding environment. Monocyte derived DC were co-cultured with resting conidia of Aspergillus fumigatus at an MOI of 5 for 12 hours, cells were sampled every three hours. RNA was extracted from both organisms at each time point and hybridised to micro-arrays, whole genome Aspergillus fumigatus array (JCVI) and a custom immune array for DC. The genes up-regulated by DC in the presence of A. fumigatus indicated that the cells were producing a pro-inflammatory response. There was an increase in IL8 expression over time confirming its association with germ tube emergence. Over the course of the experiment there was increased expression of 210 genes by A. fumigatus, GO analysis indicated significant up-regulation of the following biological processes: fermentation, drug transport, pathogenesis, transport, tyrosine catabolism and response to oxidative stress. There were two clusters of temporally regulated genes showing up regulation before 6hr and after 6 hrs. This may be related to the increased mortality exhibited in DC at 6h. The initial analysis of A. fumigatus gene expression in response to DC shows similarity to its response to neutrophils with an up-regulation in catabolism and response to oxidative stress. A. fumigatus AF293 cells were grown in the presence and absence of human dendritic cells for 0h - 12h. Hybridizations were performed with biological replicates and flip-dye pairs.

2010-07-01 | E-GEOD-22053 | biostudies-arrayexpress

Phagolysosomal proteomics identifies different macrophage activation profiles in response to Aspergillus fumigatus conidia

Project description:An Aspergillus fumigatus infection is initialized by the inhalation and germination of airborne asexual spores (conidia). Alveolar macrophages are the first immune cells to counteract an infection by phagocytosis of conidia and intracellular degradation of the pathogen. However, A. fumigatus circumvents its intracellular killing by the manipulation of the phagolysosomal maturation. With a comparative proteomic study of the phagolysosomal proteome of a virulent wild type A. fumigatus strain and an avirulent mutant strain we aimed at the identification of proteins and processes that are hijacked by the virulent strain. We found that wild type conidia strongly modulate the protein composition of the phagolysosome. Assembly and activity of vATPase, formation of lipid rafts, signal transduction pathways as well as the generation of energy and metabolites were significantly regulated in the wild type conidia containing phagolysosomes. In different experimental setups we confirmed a disassembly of the vATPase complex, reduced formation of lipid rafts and altered abundances of mTOR, MAPK signaling molecules, Rab5 and Vamp8 mediators of endosomal trafficking as well as LAMP1 and cathepsin Z lysosomal markers. Our interactome analysis indicates that A. fumigatus proteins target small GTPases of the endosomal trafficking system and signal transducers of the host, which might lead to a reduced fungicidal activity of the phagolysosome.

2018-03-08 | PXD005724 | Pride

Differentiated PLB-985 cells as a model system for Aspergillus fumigatus infection

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

mRNA-seq of Aspergillus fumigatus RNAi double knockouts

Project description:The RNA interference (RNAi) pathway has evolved numerous functionalities in eukaryotes, with many on display in Kingdom Fungi. RNAi can regulate gene expression, facilitate drug resistance, or even be altogether lost to improve virulence potential in some fungal pathogens. In the WHO fungal priority pathogen, Aspergillus fumigatus, the RNAi system is known to be intact and functional. To extend our limited understanding of A. fumigatus RNAi, we performed a multi-condition mRNA-seq analysis comparing expression of several RNAi double knockout mutants with the wild-type strain in conidia and mycelium grown for 24 or 48 hours. The analysis linked the A. fumigatus dicer-like enzymes and RNA-dependent RNA polymerases to regulation of conidial ribosome biogenesis. Cumulatively, A. fumigatus RNAi appears to play an active role in defense against double-stranded RNA species alongside a previously unappreciated housekeeping function in regulation of conidial ribosomal biogenesis genes.

2023-02-14 | GSE223618 | GEO

The In Vitro Interaction of Aspergillus fumigatus and Human immature Dendritic Cells

2010-07-01 | GSE22053 | GEO

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