Brantl, Victor Albert (2023): Die Bedeutung des Thioredoxins Aspf3 für Wachstum und Virulenz des opportunistisch humanpathogenen Schimmelpilzes Aspergillus fumigatus. Dissertation, LMU München: Faculty of Medicine |
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Abstract
Aspergillus fumigatus is an important fungal pathogen that causes allergic reactions but also life-threatening infections. One of the most abundant A. fumigatus proteins is Asp f3. This peroxiredoxin is a major fungal allergen and known for its role as a virulence factor, vaccine candidate, and scavenger of reactive oxygen species. Based on the hypothesis that Asp f3 protects A. fumigatus against killing by immune cells, we investigated the susceptibility of a conditional aspf3 mutant by employing a novel assay. Surprisingly, Asp f3-depleted hyphae were killed as efficiently as the wild type by human granulocytes. However, we identified an unexpected growth defect of mutants that lack Asp f3 under low-iron conditions, which explains the avirulence of the Δaspf3 deletion mutant in a murine infection model. A. fumigatus encodes two Asp f3 homologues which we named Af3l (Asp f3-like) 1 and Af3l2. Inactivation of Af3l1, but not of Af3l2, exacerbated the growth defect of the conditional aspf3 mutant under iron limitation, which ultimately led to death of the double mutant. Inactivation of the iron acquisition repressor SreA partially compensated for loss of Asp f3 and Af3l1. However, Asp f3 was not required for maintaining iron homeostasis or siderophore biosynthesis. Instead, we show that it compensates for a loss of iron-dependent antioxidant enzymes. Iron supplementation restored the virulence of the Δaspf3 deletion mutant in a murine infection model. Our results unveil the crucial importance of Asp f3 to overcome nutritional immunity and reveal a new biological role of peroxiredoxins in adaptation to iron limitation.
Item Type: | Theses (Dissertation, LMU Munich) |
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Keywords: | Aspf3, Aspergillus fumigatus, Peroxiredoxin, Eisensensibilität |
Subjects: | 600 Technology, Medicine 600 Technology, Medicine > 610 Medical sciences and medicine |
Faculties: | Faculty of Medicine |
Language: | German |
Date of oral examination: | 12. October 2023 |
1. Referee: | Wagener, Johannes |
MD5 Checksum of the PDF-file: | 3ebeab2cd6ba5393a7dbca9bfa8d7422 |
Signature of the printed copy: | 0700/UMD 21443 |
ID Code: | 32748 |
Deposited On: | 23. Nov 2023 11:00 |
Last Modified: | 27. Nov 2023 08:50 |