The regulation of zinc homeostasis by the ZafA transcriptional activator is essential for Aspergillus fumigatus virulence.
We have previously shown that Aspergillus fumigatus is able to grow in zinc-limiting media and that this ability is regulated at transcriptional level by both the availability of zinc and pH. When A. fumigatus grows as a pathogen, it must necessarily obtain zinc from the zinc-limiting environment provided by host tissue. Accordingly, the regulation of zinc homeostasis by some zinc-responsive transcriptional regulator in A. fumigatus must be essential for fungal growth within tissues of an immunocompromised host and, in turn, for pathogenicity. Here we provide evidence of the role of the zafA gene in regulating zinc homeostasis and its relevance in the virulence of A. fumigatus. Thus, we observed that (i) zafA can functionally replace the ZAP1 gene from Saccharomyces cerevisiae that encodes the zinc-responsive transcriptional activator Zap1 protein; (ii) the expression of zafA itself is induced in zinc-limiting media and repressed by zinc; (iii) deletion of zafA impairs the germination and growth capacity of A. fumigatus in zinc-limiting media; and (iv) the deletion of zafA abrogates A. fumigatus virulence in a murine model of invasive aspergillosis. In light of these observations, we concluded that ZafA is a zinc-responsive transcriptional activator that represents an essential attribute for A. fumigatus pathogenicity. Consequently, ZafA may constitute a new target for the development of chemotherapeutic agents against Aspergillus, because no zafA orthologues have been found in mammals.
Moreno
Miguel Angel
MA
Instituto de Microbiología-Bioquímica, Centro mixto CSIC/USAL, Departamento de Microbiología y Genética (Universidad de Salamanca). Laboratory 218. Plaza Doctores de la Reina s/n. 37007 Salamanca, Spain.
Ibrahim-Granet
Oumaima
O
Vicentefranqueira
Rocío
R
Amich
Jorge
J
Ave
Patrick
P
Leal
Fernando
F
Latgé
Jean-Paul
JP
Calera
José Antonio
JA
D000595:Amino Acid Sequence; D001232:Aspergillus fumigatus / Q000235:genetics / Q000472:pathogenicity*; D030541:Databases, Genetic; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D005800:Genes, Fungal; D008969:Molecular Sequence Data; D009154:Mutation; D019913:Nuclear Localization Signals / Q000737:chemistry; D017434:Protein Structure, Tertiary; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014774:Virulence; D015032:Zinc / Q000378:metabolism*
D005656:Fungal Proteins; D019913:Nuclear Localization Signals; D015534:Trans-Activators; D015032:Zinc