The calcineurin target CrzA regulates conidial germination, hyphal growth and pathogenesis of Aspergillus fumigatus

Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC USA; Department of Pediatrics, Duke University Medical Center, Durham, NC USA; Public Health Research Institute, International Center for Public Health, UMDNJ-New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ USA; Department of Laboratory Animal Resources, Duke University Medical Center, Durham, NC USA; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC USA; Department of Medicine, Duke University Medical Center, Durham, NC USA

^* To whom correspondence should be addressed. Email: stein022{at}mc.duke.edu.

	Abstract

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 homologue (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 but with differences compared to defects seen in the A. fumigatus cnaA (calcineurin A) strain. Like the cnaA strain, the 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 fungal-specific antifungal target for the treatment of invasive aspergillosis.