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Eukaryotic Cell, July 2008, p. 1085-1097, Vol. 7, No. 7
1535-9778/08/$08.00+0     doi:10.1128/EC.00086-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Calcineurin Target CrzA Regulates Conidial Germination, Hyphal Growth, and Pathogenesis of Aspergillus fumigatus{triangledown} ,{dagger}

Robert A. Cramer Jr.,1,{ddagger} B. Zachary Perfect,2 Nadthanan Pinchai,2 Steven Park,3 David S. Perlin,3 Yohannes G. Asfaw,4 Joseph Heitman,1,5,6 John R. Perfect,1,6 and William J. Steinbach1,2*

Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina,1 Department of Pediatrics, Duke University Medical Center, Durham, North Carolina,2 Public Health Research Institute, International Center for Public Health, UMDNJ-New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey,3 Department of Laboratory Animal Resources, Duke University Medical Center, Durham, North Carolina,4 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina,5 Department of Medicine, Duke University Medical Center, Durham, North Carolina6

Received 9 March 2008/ Accepted 17 April 2008

The calcineurin pathway is a critical signal transduction pathway in fungi that mediates growth, morphology, stress responses, and pathogenicity. The importance of the calcineurin pathway in fungal physiology creates an opportunity for the development of new antifungal therapies that target this critical signaling pathway. In this study, we examined the role of the zinc finger transcription factor Crz1 homolog (CrzA) in the physiology and pathogenicity of the opportunistic human fungal pathogen Aspergillus fumigatus. Genetic replacement of the crzA locus in A. fumigatus resulted in a strain with significant defects in conidial germination, polarized hyphal growth, cell wall structure, and asexual development that are similar to but with differences from defects seen in the A. fumigatus {Delta}cnaA (calcineurin A) strain. Like the {Delta}cnaA strain, the {Delta}crzA strain was incapable of causing disease in an experimental persistently neutropenic inhalational murine model of invasive pulmonary aspergillosis. Our results suggest that CrzA is an important downstream effector of calcineurin that controls morphology in A. fumigatus, but additional downstream effectors that mediate calcineurin signal transduction are likely present in this opportunistic fungal pathogen. In addition, the importance of CrzA to the production of disease is critical, and thus CrzA is an attractive fungus-specific antifungal target for the treatment of invasive aspergillosis.

* Corresponding author. Mailing address: Duke University Medical Center, Box 3499, Pediatric Infectious Diseases, Durham NC 27710. Phone: (919) 681-1504. Fax: (919) 684-8902. E-mail: stein022{at}mc.duke.edu

{triangledown} Published ahead of print on 2 May 2008.

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

{ddagger} Present address: Department of Veterinary Molecular Biology, Montana State University, Bozeman, MT.

Eukaryotic Cell, July 2008, p. 1085-1097, Vol. 7, No. 7
1535-9778/08/$08.00+0     doi:10.1128/EC.00086-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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