title: Mutant characterization and in vivo conditional repression identify aromatic amino acid biosynthesis to be essential for Aspergillus fumigatus virulence.
abstract: Pathogenicity of the saprobe Aspergillus fumigatus strictly depends on nutrient acquisition during infection, as fungal growth determines colonisation and invasion of a susceptible host. Primary metabolism has to be considered as a valid target for antimycotic therapy, based on the fact that several fungal anabolic pathways are not conserved in higher eukaryotes. To test whether fungal proliferation during invasive aspergillosis relies on endogenous biosynthesis of aromatic amino acids, defined auxotrophic mutants of A. fumigatus were generated and assessed for their infectious capacities in neutropenic mice and found to be strongly attenuated in virulence. Moreover, essentiality of the complete biosynthetic pathway could be demonstrated, corroborated by conditional gene expression in infected animals and inhibitor studies. This brief report not only validates the aromatic amino acid biosynthesis pathway of A. fumigatus to be a promising antifungal target but furthermore demonstrates feasibility of conditional gene expression in a murine infection model of aspergillosis.
authors.affiliation: a Research Center for Infectious Diseases; Julius-Maximilians-Universität Würzburg ; Würzburg , Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Sasse
authors.affiliation: a Research Center for Infectious Diseases; Julius-Maximilians-Universität Würzburg ; Würzburg , Germany.|b Present address: Institute of Plant Biology and Biotechnology ; University of Münster; Müunster , Germany.
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Hamer
authors.affiliation: c Department of Medicine II and Center for Interdisciplinary Clinical Research ; University Hospital Würzburg; Würzburg , Germany.
authors.forename: Jorge
authors.initials: J
authors.lastname: Amich
authors.affiliation: d Mikrobiologisches Institut - Klinische Mikrobiologie: Immunologie und Hygiene; Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg ; Erlangen , Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Binder
authors.affiliation: a Research Center for Infectious Diseases; Julius-Maximilians-Universität Würzburg ; Würzburg , Germany.|d Mikrobiologisches Institut - Klinische Mikrobiologie: Immunologie und Hygiene; Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg ; Erlangen , Germany.|e Medical Immunology Campus Erlangen; Friedrich-Alexander University Erlangen-Nürnberg ; Erlangen , Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Krappmann
mesh_terms: D024322:Amino Acids, Aromatic / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D001228:Aspergillosis / Q000188:drug therapy / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D049109:Cell Proliferation / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives; D054884:Host-Pathogen Interactions; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D014774:Virulence / Q000235:genetics; D000097797:Glyphosate
chemical_list: D024322:Amino Acids, Aromatic; D000935:Antifungal Agents; D005998:Glycine; D000097797:Glyphosate
keywords: Tet-ON; aspergillosis; conditional promoter replacement; glyphosate; primary metabolism; shikimate pathway