tetracycline and Aspergillosis

Iron is essential for a wide range of cellular processes. Here we show that the bZIP-type regulator HapX is indispensable for the transcriptional remodeling required for adaption to iron starvation in the opportunistic fungal pathogen Aspergillus fumigatus. HapX represses iron-dependent and mitochondrial-localized activities including respiration, TCA cycle, amino acid metabolism, iron-sulfur-cluster and heme biosynthesis. In agreement with the impact on mitochondrial metabolism, HapX-deficiency decreases resistance to tetracycline and increases mitochondrial DNA content. Pathways positively affected by HapX include production of the ribotoxin AspF1 and siderophores, which are known virulence determinants. Iron starvation causes a massive remodeling of the amino acid pool and HapX is essential for the coordination of the production of siderophores and their precursor ornithine. Consistent with HapX-function being limited to iron depleted conditions and A. fumigatus facing iron starvation in the host, HapX-deficiency causes significant attenuation of virulence in a murine model of aspergillosis. Taken together, this study demonstrates that HapX-dependent adaption to conditions of iron starvation is crucial for virulence of A. fumigatus.

Topics: Adaptation, Psychological; Allergens; Amino Acids; Animals; Anti-Bacterial Agents; Antigens, Plant; Aspergillosis; Aspergillus fumigatus; Basic-Leucine Zipper Transcription Factors; Biomarkers; Blotting, Northern; Disease Models, Animal; DNA, Mitochondrial; Drug Resistance, Fungal; Fungal Proteins; GATA Transcription Factors; Gene Expression Profiling; Gene Expression Regulation, Fungal; Iron Deficiencies; Mice; Oligonucleotide Array Sequence Analysis; Ornithine; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Siderophores; Survival Rate; Tetracycline; Virulence

Symptoms of bronchopneumonia developed over 4 months in a 63-year-old woman in previously good health. The symptoms worsened despite treatment with tetracycline (500 mg twice daily for 10 days). Middle-lobe pneumonia was diagnosed both clinically and radiologically, but monotherapy with ofloxacin (200 mg twice daily) was ineffective, as well as combined treatment with gentamycin (80 mg), oxacillin (1 g) and azlocillin (5 g), each three times daily intravenously. Bronchoscopy revealed obstruction of the lumen of the right middle lobe bronchus by viscous purulent secretion which contained a high count of Aspergillus fumigatus, previously found in several sputum samples. The inflammatory process regressed completely within 12 days on itraconazole (200 mg twice daily), combined with nystatin inhalation (100,000 IU five times daily). The only possible aetiologically significant risk factor in this immunocompetent woman could have been her frequent use of a bio-waste container.

Topics: Administration, Inhalation; Aspergillosis; Aspergillus fumigatus; Azlocillin; Bronchi; Bronchoscopy; Drug Therapy, Combination; Female; Gentamicins; Humans; Immunocompetence; Itraconazole; Lung Diseases, Fungal; Medical Waste Disposal; Middle Aged; Nystatin; Ofloxacin; Oxacillin; Risk Factors; Sputum; Tetracycline

Topics: Animals; Aspergillosis; Aspergillus fumigatus; Dog Diseases; Dogs; Male; Nasal Cavity; Nose Diseases; Nystatin; Tetracycline

Topics: Animals; Aspergillosis; Aspergillus; Cortisone; Injections, Subcutaneous; Lung; Mice; Species Specificity; Tetracycline

Topics: Aspergillosis; Bronchiectasis; Bronchitis; Bronchopneumonia; Cysts; Humans; Lung Abscess; Lung Diseases; Lung Neoplasms; Methacycline; Tetracycline

Topics: Aerosols; Anti-Bacterial Agents; Antifungal Agents; Aspergillosis; Bronchial Diseases; Candidiasis; Classification; Diagnosis, Differential; Humans; Lung Diseases; Lung Diseases, Fungal; Mycoses; Natamycin; Statistics as Topic; Tetracycline

Topics: Anti-Bacterial Agents; Asian People; Aspergillosis; Aspergillus; Bronchopneumonia; Humans; Liver Cirrhosis; Lung Diseases, Fungal; Pathology; Prednisolone; Tetracycline