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The regulation of zinc homeostasis by the ZafA transcriptional activator is essential for Aspergillus fumigatus virulence
Author(s) -
Moreno Miguel Ángel,
IbrahimGranet Oumaima,
Vicentefranqueira Rocío,
Amich Jorge,
Ave Patrick,
Leal Fernando,
Latgé JeanPaul,
Calera José Antonio
Publication year - 2007
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/j.1365-2958.2007.05726.x
Subject(s) - aspergillus fumigatus , biology , virulence , microbiology and biotechnology , zinc , zinc deficiency (plant disorder) , activator (genetics) , saccharomyces cerevisiae , gene , gliotoxin , transcriptional regulation , transcription factor , genetics , ecology , materials science , nutrient , metallurgy
Summary 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.