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Eukaryotic Cell, July 2006, p. 1091-1103, Vol. 5, No. 7
1535-9778/06/$08.00+0     doi:10.1128/EC.00139-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Calcineurin Controls Growth, Morphology, and Pathogenicity in Aspergillus fumigatus

William J. Steinbach,1,2,{dagger}* Robert A. Cramer Jr.,2,{dagger} B. Zachary Perfect,1 Yohannes G. Asfaw,3 Theodor C. Sauer,1 Laura K. Najvar,4 William R. Kirkpatrick,4 Thomas F. Patterson,4 Daniel K. Benjamin Jr.,1 Joseph Heitman,2,5,6 and John R. Perfect2,5

Department of Pediatrics,1 Department of Molecular Genetics and Microbiology,2 Department of Laboratory Animal Resources,3 Department of Medicine,5 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Research Drive, Durham, North Carolina 27710,6 Department of Medicine, University of Texas Health Sciences Center at San Antonio, 7703 Floyd Curl Drive, MSC 7881, San Antonio, Texas 78229-39004

Received 13 May 2006/ Accepted 15 May 2006

Calcineurin is implicated in a myriad of human diseases as well as homeostasis and virulence in several major human pathogenic microorganisms. The fungus Aspergillus fumigatus is a leading cause of infectious death in the rapidly expanding immunocompromised patient population. Current antifungal treatments for invasive aspergillosis are often ineffective, and novel therapeutic approaches are urgently needed. We demonstrate that a mutant of A. fumigatus lacking the calcineurin A (cnaA) catalytic subunit exhibited defective hyphal morphology related to apical extension and polarized growth, which resulted in drastically decreased filamentation. The {Delta}cnaA mutant lacked the extensive lattice of invading hyphae seen with the wild-type and complemented strains. Sporulation was also affected in the {Delta}cnaA mutant, including morphological conidial defects with the absence of surface rodlets and the added presence of disjunctors creating long conidial chains. Infection with the {Delta}cnaA mutant in several distinct animal models with different types of immunosuppression and inoculum delivery led to a profound attenuation of pathogenicity compared to infection with the wild-type and complemented strains. Lung tissue from animals infected with the {Delta}cnaA mutant showed a complete absence of hyphae, in contrast to tissue from animals infected with the wild-type and complemented strains. Quantitative fungal burden and pulmonary infarct scoring confirmed these findings. Our results support the clinical observation that substantially decreasing fungal growth can prevent disease establishment and decrease mortality. Our findings reveal that calcineurin appears to play a globally conserved role in the virulence of several pathogenic fungi and yet plays specialized roles in each and can be an excellent target for therapeutic intervention.

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

{dagger} W.J.S. and R.A.C. contributed equally to this work.

Eukaryotic Cell, July 2006, p. 1091-1103, Vol. 5, No. 7
1535-9778/06/$08.00+0     doi:10.1128/EC.00139-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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