Calcineurin controls growth, morphology, and pathogenicity in Aspergillus fumigatus.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Steinbach, WJ; Cramer, RA; Perfect, BZ; Asfaw, YG; Sauer, TC; Najvar, LK; Kirkpatrick, WR; Patterson, TF; Benjamin, DK; Heitman, J; Perfect, JR

Published Date

  • July 2006

Published In

Volume / Issue

  • 5 / 7

Start / End Page

  • 1091 - 1103

PubMed ID

  • 16835453

Pubmed Central ID

  • 16835453

International Standard Serial Number (ISSN)

  • 1535-9778

Digital Object Identifier (DOI)

  • 10.1128/EC.00139-06

Language

  • eng

Conference Location

  • United States