This study indicates that IDH1 codon 132 mutation is closely linked to the genomic profile of the tumor and constitutes an important prognostic marker in grade 2 to 4 gliomas.
The air we breathe is filled with thousands of fungal spores (conidia) per cubic metre, which in certain composting environments can easily exceed 10(9) per cubic metre. They originate from more than a hundred fungal species belonging mainly to the genera Cladosporium, Penicillium, Alternaria and Aspergillus. Although these conidia contain many antigens and allergens, it is not known why airborne fungal microflora do not activate the host innate immune cells continuously and do not induce detrimental inflammatory responses following their inhalation. Here we show that the surface layer on the dormant conidia masks their recognition by the immune system and hence prevents immune response. To explore this, we used several fungal members of the airborne microflora, including the human opportunistic fungal pathogen Aspergillus fumigatus, in in vitro assays with dendritic cells and alveolar macrophages and in in vivo murine experiments. In A. fumigatus, this surface 'rodlet layer' is composed of hydrophobic RodA protein covalently bound to the conidial cell wall through glycosylphosphatidylinositol-remnants. RodA extracted from conidia of A. fumigatus was immunologically inert and did not induce dendritic cell or alveolar macrophage maturation and activation, and failed to activate helper T-cell immune responses in vivo. The removal of this surface 'rodlet/hydrophobin layer' either chemically (using hydrofluoric acid), genetically (DeltarodA mutant) or biologically (germination) resulted in conidial morphotypes inducing immune activation. All these observations show that the hydrophobic rodlet layer on the conidial cell surface immunologically silences airborne moulds.
IDH mutation appears to be a significant marker of positive prognosis and chemosensitivity in low-grade gliomas, independently of 1p-19q codeletion, whereas its impact on the course of untreated tumors seems to be limited.
SummaryPulmonary infections due to Aspergillus fumigatus result from the development of a colony of tightly associated hyphae in contact with the air, either in the alveoli (invasive aspergillosis) or in an existing cavity (aspergilloma). The fungal ball observed in vivo resembles an aerial colony obtained in agar medium in vitro more than a mycelial mass obtained in liquid shaken conditions that have been classically used to date to study A. fumigatus physiology. For this reason, we embarked on an analysis of the characteristics of A. fumigatus colonies grown in aerial static conditions. (i) Under static aerial conditions, mycelial growth is greater than in shaken, submerged conditions. (ii) The colony surface of A. fumigatus revealed the presence of an extracellular hydrophobic matrix that acts as a cohesive linkage bonding hyphae into a contiguous sheath. (iii) The extracellular matrix is composed of galactomannan, a1,3 glucans, monosaccharides and polyols, melanin and proteins including major antigens and hydrophobins. (iv) A. fumigatus colonies were more resistant to polyenes than shake, submerged mycelium. This is the first analysis of the three dimensional structure of a mycelial colony. Knowledge of this multicellular organization will impact our future understanding of the pathobiology of aerial mold pathogens.
This exclusive association suggests a new mechanism of tumorigenesis. Perhaps the IDH1/IDH2 mutation is a prerequisite for the occurrence of the t(1;19) translocation, or it is required for the 1p19q codeleted cells to acquire a tumor phenotype.
The surface of Aspergillus fumigatus conidia, the first structure recognized by the host immune system, is covered by rodlets. We report that this outer cell wall layer contains two hydrophobins, RodAp and RodBp, which are found as highly insoluble complexes. The RODA gene was previously characterized, and ⌬rodA conidia do not display a rodlet layer (N. Thau, M. Monod, B. Crestani, C. Rolland, G. Tronchin, J. P. Latgé, and S. Paris, Infect. Immun. 62:4380-4388, 1994). The RODB gene was cloned and disrupted. RodBp was highly homologous to RodAp and different from DewAp of A. nidulans. ⌬rodB conidia had a rodlet layer similar to that of the wild-type conidia. Therefore, unlike RodAp, RodBp is not required for rodlet formation. The surface of ⌬rodA conidia is granular; in contrast, an amorphous layer is present at the surface of the conidia of the ⌬rodA ⌬rodB double mutant. These data show that RodBp plays a role in the structure of the conidial cell wall. Moreover, rodletless mutants are more sensitive to killing by alveolar macrophages, suggesting that RodAp or the rodlet structure is involved in the resistance to host cells.The surface of many fungal conidia is covered by a thin layer of regularly arranged rodlets. This structure, which favors air buoyancy and dispersion of the conidia by air currents (2), is mainly proteinaceous (3,(8)(9)(10)16). The proteins present in the cell wall of aerial structures of fungi responsible for this rodlet configuration are the hydrophobins, a family of small, moderately hydrophobic proteins characterized by the conserved spacing of eight cysteine residues (42, 44). For the human opportunistic pathogen Aspergillus fumigatus, the presence of a rodlet layer has been visualized and the RODA gene has been previously shown to be involved in the formation of the rodlets of its conidia (41). In plants, hydrophobins have been associated with the virulence of phytopathogenic fungi (38). Although it has been repeatedly shown that cell wall and associated structures help human fungal pathogens to resist host defense reactions (22), to date no studies have analyzed the role of the rodlet layer in the resistance of the conidia to phagocytosis. Even though the rodlet layer of the conidia of Neurospora crassa, Beauveria bassiana, and Magnaporthe grisea contained a single hydrophobin (5, 39, 40), A. nidulans, a species phylogenetically close to A. fumigatus, has two conidial hydrophobins, RodAp and DewAp (35,36). These data have prompted us to reexamine the surface layer of the conidia of A. fumigatus with a view to (i) analyzing exhaustively hydrophobins present on the surface of the conidia and (ii) studying their role in resistance to phagocytosis. A. fumigatus is a good model for the later study, since conidia, which are a main component of the airborne thermophilic fungal florae (1), are all engulfed and killed by lung alveolar macrophages (AM) following their inhalation (11; B. Philippe, O. Ibrahim-Granet, M. C. Prévost, M. A. Gougerot-Pocidalo, J. Roes, M. SanchezPerez, A. Van der Meer...
Upon infection of a host, the pathogenic fungus Aspergillus fumigatus is attacked by the reactive oxygen species produced by phagocytic cells. Detoxification of hydrogen peroxide by catalases was proposed as a way to overcome this host response. A. fumigatus produces three active catalases; one is produced by conidia, and two are produced by mycelia. The mycelial catalase Cat1p was studied previously. Here we characterized the two other catalases, their genes, and the phenotypes of gene-disrupted mutants. CatAp, a spore-specific monofunctional catalase, is resistant to heat, metal ions, and detergent. This enzyme is a dimeric protein with 84.5-kDa subunits. The 749-amino-acid polypeptide exhibits high levels of similarity to the Aspergillus nidulans CatA catalase and to bacterial catalase HPII of Escherichia coli. In spite of increased sensitivity to H 2 O 2 , killing of ⌬catA conidia by alveolar macrophages and virulence in animals were similar to the killing of conidia by alveolar macrophages and virulence in animals observed for the wild type. In contrast to the Cat1p and CatAp catalases, the mycelial Cat2p enzyme is a bifunctional catalase-peroxidase and is sensitive to heat, metal ions, and detergent. This enzyme, an 82-kDa monomer, is homologous to catalase-peroxidases of several fungi and bacteria. Surprisingly, mycelium of the double ⌬cat1⌬cat2 mutant with no catalase activity exhibited only slightly increased sensitivity to H 2 O 2 and was as sensitive to killing by polymorphonuclear neutrophils as mycelium of the wild-type strain. However, this mutant exhibited delayed infection in the rat model of aspergillosis compared to infection by the wild-type strain. These results indicate that conidial catalase is not a virulence factor and that mycelial catalases transiently protect the fungus from the host.The opportunistic fungal pathogen Aspergillus fumigatus is responsible for a variety of respiratory diseases in humans, such as allergic bronchopulmonary aspergillosis, aspergilloma, and invasive aspergillosis (10). This fungus is an airborne saprophyte that is inhaled by every human. Alveolar macrophages and polymorphonuclear cells, cellular components of the innate defense of the lung, cooperate to control and eliminate the fungus in the airways. Macrophages eliminate conidia, and protection against the hyphal form is mediated by polymorphonuclear cells (41). Reactive oxygen species (ROS) produced by alveolar macrophages play an essential role in the killing of A. fumigatus conidia (38a). Moreover, in vitro studies of neutrophil function have shown that hydrogen peroxide effectively kills fungal hyphae (12) and that neutrophil-mediated damage is blocked by addition of a commercial catalase (13). Accordingly, catalase, which is a good scavenger of H 2 O 2 , was considered to be a putative virulence factor of A. fumigatus that could counteract the oxidative defense reactions of the host phagocytes (20). No conidial catalase has been identified previously in A. fumigatus. In Aspergillus nidulans, however, a...
Altogether our results uncovered a small noncoding RNA signature in microvesicles isolated from GBM patient serum that could be used as a fast and reliable differential diagnostic biomarker.
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