Eukaryotic Cell
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Eukaryotic Cell, December 2007, p. 2290-2302, Vol. 6, No. 12
1535-9778/07/$08.00+0     doi:10.1128/EC.00267-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Aspergillus fumigatus Transcriptional Regulator AfYap1 Represents the Major Regulator for Defense against Reactive Oxygen Intermediates but Is Dispensable for Pathogenicity in an Intranasal Mouse Infection Model{triangledown} ,{dagger}

Franziska Lessing,1,2 Olaf Kniemeyer,1,2 Iwona Wozniok,3 Juergen Loeffler,3 Oliver Kurzai,4 Albert Haertl,5 and Axel A. Brakhage1,2*

Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology-Hans-Knoell-Institute, Jena, Germany,1 Department of Microbiology and Molecular Biology, Friedrich-Schiller-University, Jena, Germany,2 University of Wuerzburg, Medical Clinic II, Wuerzburg, Germany,3 University of Wuerzburg, Institute of Hygiene and Microbiology, Wuerzburg, Germany,4 Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology-Hans-Knoell-Institute, Jena, Germany5

Received 25 July 2007/ Accepted 24 September 2007

Macrophages and neutrophils kill the airborne fungal pathogen Aspergillus fumigatus. The dependency of this killing process on reactive oxygen intermediates (ROI) has been strongly suggested. Therefore, we investigated the enzymatic ROI detoxifying system by proteome analysis of A. fumigatus challenged by H2O2. Since many of the identified proteins and genes are apparently regulated by a putative Saccharomyces cerevisiae Yap1 homolog, the corresponding gene of A. fumigatus was identified and designated Afyap1. Nuclear localization of a functional AfYap1-eGFP fusion was stress dependent. Deletion of the Afyap1 gene led to drastically increased sensitivity of the deletion mutant against H2O2 and menadione, but not against diamide and NO radicals. Proteome analysis of the {Delta}Afyap1 mutant strain challenged with 2 mM H2O2 indicated that 29 proteins are controlled directly or indirectly by AfYap1, including catalase 2. Despite its importance for defense against reactive agents, the Afyap1 deletion mutant did not show attenuated virulence in a murine model of Aspergillus infection. These data challenge the hypothesis that ROI such as superoxide anions and peroxides play a direct role in killing of A. fumigatus in an immunocompromised host. This conclusion was further supported by the finding that killing of A. fumigatus wild-type and {Delta}Afyap1 mutant germlings by human neutrophilic granulocytes worked equally well irrespective of whether the ROI scavenger glutathione or an NADPH-oxidase inhibitor was added to the cells.

* Corresponding author. Mailing address: Leibniz Institute for Natural Product Research and Infection Biology, Beutenbergstrasse 11a, 07745 Jena, Germany. Phone: 49 3641 656601. Fax: 49 3641 656603. E-mail: Axel.Brakhage{at}hki-jena.de

{triangledown} Published ahead of print on 5 October 2007.

{dagger} Supplemental material for this article may be found at http://ec.asm.org/.

Eukaryotic Cell, December 2007, p. 2290-2302, Vol. 6, No. 12
1535-9778/07/$08.00+0     doi:10.1128/EC.00267-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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