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Infection and Immunity, September 2004, p. 5193-5203, Vol. 72, No. 9
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.9.5193-5203.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The Cyclic AMP-Dependent Protein Kinase A Network Regulates Development and Virulence in Aspergillus fumigatus

Burghard Liebmann,1 Meike Müller,2 Armin Braun,2 and Axel A. Brakhage1*

Institut für Mikrobiologie, Universität Hannover,1 Fraunhofer Institut für Toxikologie und Experimentelle Medizin, Hannover, Germany2

Received 15 December 2003/ Returned for modification 15 January 2004/ Accepted 11 May 2004

Aspergillus fumigatus is an important pathogen of immunocompromised hosts, causing pneumonia and invasive disseminated disease with high mortality. To determine the importance of the cyclic AMP (cAMP) signaling pathway for virulence, the pkaC1 gene encoding a protein kinase A (PKA) catalytic subunit was cloned and characterized. Deletion of pkaC1 led to reduced conidiation and growth. PKA activity was not detectable in {Delta}pkaC1, {Delta}gpaB, and {Delta}acyA mutant strains. gpaB and acyA encode a G protein {alpha} subunit involved in cAMP signal transduction and adenylate cyclase, respectively. Addition of cAMP led to PKA activity in crude extracts of both the {Delta}gpaB and {Delta}acyA strains but not in crude extracts of the {Delta}pkaC1 strain. These findings provide evidence that PKAC1 represents the predominant form of PKA under the conditions tested, and GPAB and ACYA are members of the cAMP signaling cascade. Analysis of a pksPp-lacZ gene fusion indicated that the expression of the pathogenicity determinant-encoding pksP gene was reduced in {Delta}pkaC1 mutant strains compared with the expression of the gene fusion in the parental strain. In a low-dose murine inhalation model, conidia of both the {Delta}pkaC1 and {Delta}gpaB mutant strains were almost avirulent. Taken together, these findings indicate that the cAMP-PKA signal transduction pathway is required for A. fumigatus pathogenicity.

* Corresponding author. Mailing address: Institut für Mikrobiologie, Universität Hannover, Schneiderberg 50, D-30167 Hannover, Germany. Phone: 49 511 762 5945. Fax: 49 511 762 5287. E-mail: Brakhage{at}ifmb.uni-hannover.de.

Editor: T. R. Kozel

Infection and Immunity, September 2004, p. 5193-5203, Vol. 72, No. 9
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.9.5193-5203.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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