The role of siderophores in iron uptake and virulence of the opportunistic fungal pathogen : Aspergillus fumigatus
Bibliographic record
Abstract
Aspergillus fumigatus is an opportunistic fungal pathogen that can cause lifethreatening invasive aspergillosis and is a leading cause of mortality in bone marrow and lung transplant recipients.Currently, the mortality rate of invasive aspergillosis is approximately 50%.The virulence factors of Aspergillus species remain largely unknown.The purpose of this research was to determine the mechanism(s) by which A.fumigatus survives within the iron-limiting environment of the host.A. fumigatus conidia germinated and grew extremely well in the presence of human serum, which is normally fungistatic 'due to the presence of the iron-binding protein, transferrin.This result implied that A. fumigatus possesses highly effective mechanisms for iron uptake.A. fumigatus was able to remove transferrin-bound iron across a dialysis membrane, indicating that molecules el0 kDa were responsible for iron acquisition.Siderophores, which are small iron-binding molecules, were detected during the first 8 hours of culture.Several hydroxamate siderophores were purified from A.fumigatus cultures, and the most abundant were identified as N'N"N9"triacetylfusarinine C (TAF) and ferricrocin.The individual microscopic rate constants for removal of iron from the two ironbinding sites on human transferrin were calculated for both TAF and ferricrocin.Both A. fumigatus siderophores could remove iron from all transferrin species, but preferentially removed C-terminal iron.The rates of iron removal from diferric transferrin were 2.4 -1- iii 0.2 M-'min-' for TAF and 1.6 + 0.3 M-'mid' for ferrkrocin.These rates were similar to those of bacterial siderophores which are known virulence factors.A siderophore secretion mutant was constructed in A. fumigatus by deletion of sidA, which encodes L-ornithine ~~-o x ~~e n a s e , the first committed step in siderophore biosynthesis.This mutant was unable to grow in low iron medium, or in medium containing serum.It was also unable to remove iron from human diferric transferrin.The sidA mutant showed significantly reduced virulence in a mouse model of invasive aspergillosis.In conclusion, hydroxamate siderophores produced by A. fumigatus play an important role in iron uptake in vivo.Therefore, siderophores represent one of the few virulence factors identified in A. fumigatus.The siderophore-iron uptake pathway represents a potential target for anti-Aspergillus drug development. DEDICATIONThis thesis is dedicated to my children Max and Sophie Hissen, who bring smiles and laughter to every day.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".