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Figure 1: Early evolutionary events in fungi as related to eukaryotic hosts and symbionts

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Target genes of the hypoxic regulator SrbA have not been studied in fully detail yet and global transcript profiling of the response of pathogenic fungi to low oxygen levels revealed a relative heterogeneous picture on hypoxia-responsive genes. In the pathogenic dimorphic yeast Candida albicans, genes involved in fermentative metabolism were up-regulated, whereas genes regulating oxidative metabolism were down-regulated by hypoxia.() By contrast, the transcript levels of respiratory genes increased in C. neoformans during exposure to hypoxic growth conditions.() In A. fumigatus, transcriptional profiling of the srbA null mutant revealed an SrbA-dependent regulation of genes involved in ergosterol biosynthesis, cell wall biosynthesis and transport processes.() In contrast, regulation of the hypoxic response on the level of proteins has not been elucidated in A. fumigatus or any other important human-pathogenic fungi yet. For this reason, we carried out global analysis of the change of the A. fumigatus proteome during hypoxia by two-dimensional gel fluorescence gel electrophoresis (DIGE). Because of the advantages in generating more reproducible, reliable and biologically homogeneous data sets, we used an oxygen-controlled chemostat() to cultivate A. fumigatus either under normoxic (21% O2) or under hypoxic (0.2% O2) conditions. By our proteome analysis we have shown that A. fumigatus compensates the depletion of molecular oxygen by the increased production of respiratory proteins and that a link exists between hypoxia and nitrosative stress. Furthermore, for the first time we report that hypoxia is able to induce the activation of an otherwise silent secondary metabolite gene cluster in A. fumigatus.

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The environmental mold Aspergillus fumigatus has become the most important airborne fungal pathogen of humans and is the second most frequent cause of systemic fungal infections.() In immunocompetent individuals, A. fumigatus can cause allergic reactions and noninvasive infections such as aspergilloma. However, in immunocompromised patients, this filamentous fungus is the main causative agent for life-threatening systemic infections named invasive aspergillosis (IA). Due to the improvements in transplant medicine and the therapy of hematological malignancies, the number of patients and thus the quantity of cases of IA has increased significantly in the last decades. Specific diagnostics are still limited, as are the possibilities of therapeutic intervention, leading to a high mortality rate of 30 up to 90% for IA., Infection is most commonly initiated by inhalation of airborne fungal spores (conidia), which germinate in the lung alveoli and the formed hyphae start to grow invasively into the lung tissue. Accumulating evidence suggests that A. fumigatus experiences hypoxia while growing in the lung. The oxygen partial pressure within the alveoli averages at 7.9 kPa (19.7 kPa in the atmosphere). In the surrounding tissue, it drops down to 2−4 kPa and in inflamed, necrotic areas even down to 0.13 kPa.() This can lead on one hand to a general reduction of phagocyte killing by the host, but on the other hand may promote the availability of free iron for the pathogen due to a decrease in redox potential.() Additionally, nitric oxide (NO) secreted by cells of the innate immune system, such as macrophages, acts as an inhibitor of cellular respiration and can cause so-called metabolic hypoxia.() Thus, it is obvious that A. fumigatus has to adapt to low oxygen partial pressures during the infection. However, the fungus is considered to be an obligate aerobe and there is no clear evidence for either a fermentative metabolism or anaerobic respiration in A. fumigatus. Nevertheless, some hints for ethanol fermentation during A. fumigatus infection were obtained in a murine model of IA() and A. fumigatus was shown to be capable of growing at low oxygen concentrations between 0.1% (v/v) and 0.5% (v/v) on agar plates.() Under these conditions, the fungus faces the challenge to maintain the homeostasis of ergosterol and other cellular components, such as NAD and heme, whose biosyntheses require molecular oxygen.()

The mold Aspergillus fumigatus is the most important airborne fungal pathogen. Adaptation to hypoxia represents an important virulence attribute for A. fumigatus. Therefore, we aimed at obtaining a comprehensive overview about this process on the proteome level. To ensure highly reproducible growth conditions, an oxygen-controlled, glucose-limited chemostat cultivation was established. Two-dimensional gel electrophoresis analysis of mycelial and mitochondrial proteins as well as two-dimensional Blue Native/SDS-gel separation of mitochondrial membrane proteins led to the identification of 117 proteins with an altered abundance under hypoxic in comparison to normoxic conditions. Hypoxia induced an increased activity of glycolysis, the TCA-cycle, respiration, and amino acid metabolism. Consistently, the cellular contents in heme, iron, copper, and zinc increased. Furthermore, hypoxia induced biosynthesis of the secondary metabolite pseurotin A as demonstrated at proteomic, transcriptional, and metabolite levels. The observed and so far not reported stimulation of the biosynthesis of a secondary metabolite by oxygen depletion may also affect the survival of A. fumigatus in hypoxic niches of the human host. Among the proteins so far not implicated in hypoxia adaptation, an NO-detoxifying flavohemoprotein was one of the most highly up-regulated proteins which indicates a link between hypoxia and the generation of nitrosative stress in A. fumigatus.