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Harris, S. Polarity in filamentous fungi: moving beyond the yeast paradigm. Galagan, J. RIP: the evolutionary cost of genome defense. Trends Genet. Download references. The authors would like to thank M. Zody, X. Xie, M. Kamal, J. Taylor, G. Turgeon and E. Lander for numerous helpful conversations, comments and critical readings of the paper.
We also thank all members of the sequencing platform at the Broad Institute. We thank R. Dean for providing the BAC library used in sequencing. We especially thank M. Brudno for his help in using Mlagan to align the three genomes, and R. Morris for his many contributions to the A. Author Contributions B. Batzoglou and S. Farman analysed telomeres and subtelomeric gene content. Momany analysed hyphal growth and RhoGTPases. Machida provided the sequence and annotation for A.
James E. Galagan, Sarah E. Gerhard H. David B. You can also search for this author in PubMed Google Scholar. Correspondence to James E. Reprints and permissions information is available at npg. The authors declare no competing financial interests. The data and description of methods used to derive the phylogenetic relationship of the the three Aspergilli XLS kb. Description of Hierarchical Synteny Clustering method, detailed discussion of sytenic breaks near to repeats and telomeres, description of fit of genome breakage to random break model, data supporting lack of decelerated evolution in A.
Description of methods for uORF comparative analysis. XLS kb. Description of methods used for prediction of Non-coding conserved patterns.
List of all patterns, locations of patterns, and known Aspergillus and yeast transcription factor binding sites. Description of A. DOC 49 kb. Reprints and Permissions. Sequencing of Aspergillus nidulans and comparative analysis with A. Download citation. Received : 31 May Accepted : 19 October Issue Date : 22 December Anyone you share the following link with will be able to read this content:.
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Download PDF. Abstract The aspergilli comprise a diverse group of filamentous fungi spanning over million years of evolution. You have full access to this article via your institution. Main The aspergilli are a ubiquitous group of filamentous fungi spanning over million years of evolution.
Genome assembly and annotation The genome sequence of A. Phylogenetic relationship Previous work based on large subunit rDNA data has led to a widely accepted phylogeny of the aspergilli in which A. Figure 1: Phylogenetic tree and representative dot plot. Full size image. Overall genome and proteome comparison Although in the same genus, the three aspergilli differ considerably in their genome sequences.
Table 1 Comparison of genome characteristics Full size table. Conserved synteny and genome evolution These three aspergilli provide an opportunity to study eukaryotic genome evolution over a divergence approaching the limit of conserved long-range synteny.
Table 2 Characteristics of pairwise conserved synteny Full size table. Figure 2: Aspergillus comparative map. Figure 3: Rates of branch-specific rearrangements.
Furthermore, studies have shown that patients infected with A. Nidulans usually manifest a strong drug resistance. However, specific antifungal drugs that aim to treat A. Nidulans infection have not been developed yet. Therefore, it is an urgent need to exploit more effective antifungal drugs for the treatment of A.
Nidulans infection. Having worked in the field for many years, Creative Biolabs has successfully developed multiple advanced technology platforms for antifungal drug discovery. Moreover, the services we provided are characterized by:. Besides A. Nidulans , we also provide antifungal drug discovery services against other pathogens that can also cause human infections, which including but not limited to A. Fumigates , A.
Flavus , A. Terreus , and A. For more detailed information, please feel free to contact us. Product Service. In the reported cases, fungal species were isolated: A.
Focusing on the Aspergillus species, A. Aspergillus nidulans seems to have a remarkable unique interaction with CGD patients, as it remains a rare pathogen among other risk groups. In the neutropenic host, only 3 cases have been described: 2 pulmonary IA with highly resistant strains [ 12 , 13 ] and a primary cutaneous infection associated with a Hickman catheter [ 14 ].
Overall, as disease pathology and progression are the results of the complex interaction between the pathogen and the host, exploring the host—fungus interface will result in more insight and detailed understanding of this challenging frontline, in order to optimize diagnostic and therapeutic strategies. Identification of A. Aspergillus nidulans is a homothallic species capable of producing the teleomorph sexual stage without mating studies. The dual nomenclature of members of the Aspergillus section Nidulanti may be confusing for the clinician, as the ability of the fungus to produce a sexual state depends on the culture conditions.
The application of molecular tools has had major impact on the taxonomy of fungi. Multilocus sequence-based phylogenetic analyses have emerged as the primary tool for inferring phylogenetic species boundaries and relationships within subgenera and sections. The efficacy of antifungal agents is different for the various Aspergillus spp. Minimum inhibitory concentrations MICs for the mold-active azoles show a good susceptibility profile of A. Although a pediatric dosage has not been defined, posaconazole as salvage therapy in CGD shows to be safe and effective [ 21 , 22 ].
Detailed molecular analysis of 33 international clinical isolates of Emericella spp. Both species are associated with clearly distinct susceptibility patterns, especially to amphotericin B median MICs 2.
These observed differences in activity might be clinically important, highlighting the relationship between correct species identification and susceptibility testing. Twenty-five cases of IA due to A. The major clinical features are summarized in Table 2.
Twenty-three were male, and median age was 7. The presenting signs and symptoms were often mild, with low-grade fever, local pain or swelling, malaise, and cough, but could be completely silent with asymptomatic new lung infiltrates detected during a routine visit.
Computed tomography scan of A. Note the extensive chest wall invasion and subcutaneous infiltration arrow. Information on diagnostic tools was provided in 22 of the 25 patients reviewed in this study. Twenty-one of them fulfilled the criteria for proven invasive mold infection. Computed tomography and magnetic resonance established extra-pulmonary extension to soft tissues, bones, and spinal cord injury.
Local extension of disease from lung parenchyma to adjacent structures and osteomyelitis of the thoracic skeleton have been found particularly associated with underlying CGD [ 24 ]. In 4 of the reported CGD cases, information about circulating antigens in serum could be extracted [ 25—28 ]. Three of them were negative despite the extensiveness of the disease. Information on diagnostic polymerase chain reaction was retrieved in 2 proven cases and 1 probable; however, results were negative or inconclusive [ 25 , 27 , 29 ].
Four cases mentioned strongly positive anti- Aspergillus antibodies [ 26 , 30—32 ]. All patients except 2 received presumptive treatment with amphotericin B. Conventional amphotericin B deoxycholate range, 0. Use of voriconazole was first reported in and used in 5 cases, only once as a first-line treatment [ 33 ].
In those who did not receive surgery and survived, infection was limited to the lung or with minimal involvement of adjacent structures [ 29 , 34 ].
The exact mortality rate of A. By comparing invasive A. Besides the fact that comparable fatal A. Most studies focusing on innate immune responses against Aspergillus spp. Knowledge of the host response against other Aspergillus spp. The first line of host—defense is directed against conidia, the infective form of the filamentous fungi, and consists of macrophages.
The macrophages will kill the germinating spores intracellularly by mainly nonoxidative processes. The second line of defense against mold infections is superoxide production by neutrophils, a powerful mechanism to kill the invasive hyphal structures of filamentous fungi such as Aspergillus spp. A functional NADPH-oxidase is crucial both as antimicrobial effector complex and as regulator of inflammation: a balance that is skewed to a state of hyperinflammation upon interaction with A.
Various mechanisms known to play a role in the host immune response induced by A. A , Inhaled A. Influence of A. L-tryptophan metabolism in human CGD cells is normal in response to fungal pathogens; however, ILA is strikingly low in response to A. Infection of human CGD leucocytes with A.
Furthermore, inhibitors of NADPH-oxidase that decreased the production of reactive oxidant intermediates inhibited the killing of A. By comparing the killing ratio of A. Although differences in animal strains, morphotypes, cell sources, and methods to assay the fungal damage might be responsible for this discrepancy, this heterogeneity underscores the complexity of fungal resistance and the fact that other mechanisms than killing by ROS must be involved as well.
Reactive-oxygen species like H 2 O 2 seem to act as chemoattractants [ 44 ]. Furthermore, by studying IA in an experimental murine model, it was suggested that early polymorphonuclear neutrophil PMN recruitment is crucial. In vitro infection of circulating human leucocytes revealed that resistance to A. We showed that A. These results indicate that the etiology of A. In the early s, it was suggested that abnormal pH regulation within the phagosome of CGD phagocytes might have a role in defective killing [ 45 ].
The basis of this assumption was that the initiation of superoxide production is normally accompanied by phagosomal alkalinization as a result of the proton-acceptor function of superoxide anions. This pH change was proposed to be essential for the activation of granule-derived enzymes within the phagosome. Later on, this scheme was adjusted by showing that it is the pH-dependent, compensatory potassium surge across the vacuolar membrane, which is responsible for the release and activation of cationic granule proteins, form the anionic sulfated proteoglycan matrix [ 41 ].
In patients with CGD, however, the NADPH-oxidase function, alkalinization, and potassium influx is absent, resulting in impairment of these killing mechanisms. Whether this plays a significant role in the pathogenesis of A. Interestingly, the use of pH-response mutants of A. This observation shows that extrapolation of data from neutropenic mouse models of IA is insufficient to understand the pathophysiology of IA in CGD patients. Phagocytic cells possess several nonoxidative fungal mechanisms, including antimicrobial peptides eg, defensins, histatin 5 and hydrolases, which are effective in preventing germination or at killing intra- and extracellular fungi [ 53 ].
Drosomycin-like defensin shows antifungal activity [ 54 ]. This synthetic drosomycin-like defensin was designated based on a putative human homologue of the Drosophila -derived drosomycin, known for its antifungal properties.
In this in vitro study, the susceptibility of A. In contrast, A. The role of defensins and other cationic proteins stored in the granules of phagocytes from CGD patients in the host defense against filamentous fungi is not yet known and needs to be investigated. It is clear that the almost exclusive contribution of NADPH-oxidase to microbial killing is a justified subject of debate, and recent studies indicate a critical role of the NADPH-oxidase as regulator of the immune homeostasis at multiple levels [ 55—57 ].
We have observed that the absence of the respiratory burst is associated with a dysregulated production of pro- and anti-inflammatory cytokines and further contributes to the pathogenesis of IA in CGD patients [ 58 ]. A more proinflammatory cytokine response was shown after stimulation with A.
The opposite was seen in healthy controls. In a paper by Romani et al. However, in humans with CGD, tryptophan metabolism was shown to be intact, indicating that the mechanism of fungal susceptibility is different in CGD humans from CGD mice [ 59—60 ].
Indeed, in contrast to mice, both CGD genotypes display a normal tryptophan metabolism.
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