The Aspergillus fumigatus transcriptional activator CpcA contributes significantly to the virulence of this fungal pathogen.
We have cloned and characterized the Aspergillus fumigatus cpcA gene encoding the transcriptional activator of the cross-pathway control system of amino acid biosynthesis. cpcA encodes a functional orthologue of Saccharomyces cerevisiae Gcn4p. The coding sequence of the 2.2 kb transcript is preceded by two short upstream open reading frames, the larger one being well conserved among Aspergilli. Deletion strains in which either the coding sequence or the entire locus are replaced by a bifunctional dominant marker are impaired in their cross-pathway control response upon amino acid starvation, as demonstrated by analyses of selected reporter genes and specific enzymatic activities. In a murine model of pulmonary aspergillosis, cpcAdelta strains display attenuated virulence. Pathogenicity is restored to wild-type levels in strains with reconstitution of the genomic locus. Competitive mixed infection experiments additionally demonstrate that cpcAdelta strains are less able to survive in vivo than their wild-type progenitor. Our data suggest that specific stress conditions are encountered by A. fumigatus within the mammalian host and that the fungal cross-pathway control system plays a significant role in pulmonary aspergillosis.
Krappmann
Sven
S
Department of Molecular Microbiology and Genetics, Institute for Microbiology and Genetics, Georg-August-University Göttingen, Grisebachstr. 8, D-37077 Göttingen, Germany.
Bignell
Elaine M
EM
Reichard
Utz
U
Rogers
Tom
T
Haynes
Ken
K
Braus
Gerhard H
GH
D000595:Amino Acid Sequence; D000818:Animals; D001232:Aspergillus fumigatus / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D050976:Basic-Leucine Zipper Transcription Factors; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D016415:Sequence Alignment; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D050976:Basic-Leucine Zipper Transcription Factors; C104754:CPCA protein, Aspergillus niger; D005656:Fungal Proteins; D014157:Transcription Factors