title: Calcineurin target CrzA regulates conidial germination, hyphal growth, and pathogenesis of Aspergillus fumigatus.
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 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 DeltacnaA (calcineurin A) strain. Like the DeltacnaA strain, the DeltacrzA 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.
authors.affiliation: Duke University Medical Center, Box 3499, Pediatric Infectious Diseases, Durham, NC 27710, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cramer
authors.forename: B Zachary
authors.initials: BZ
authors.lastname: Perfect
authors.forename: Nadthanan
authors.initials: N
authors.lastname: Pinchai
authors.forename: Steven
authors.initials: S
authors.lastname: Park
authors.forename: David S
authors.initials: DS
authors.lastname: Perlin
authors.forename: Yohannes G
authors.initials: YG
authors.lastname: Asfaw
authors.forename: Joseph
authors.initials: J
authors.lastname: Heitman
authors.forename: John R
authors.initials: JR
authors.lastname: Perfect
authors.forename: William J
authors.initials: WJ
authors.lastname: Steinbach
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001228:Aspergillosis / Q000378:metabolism / Q000382:microbiology* / Q000503:physiopathology; D001232:Aspergillus fumigatus / Q000166:cytology / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002473:Cell Wall / Q000378:metabolism; D004268:DNA-Binding Proteins; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D025301:Hyphae / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D016415:Sequence Alignment; D015398:Signal Transduction; D013172:Spores, Fungal / Q000166:cytology / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016335:Zinc Fingers
chemical_list: C109868:CRZ1 protein, S cerevisiae; C530975:CrzA protein, Aspergillus fumigatus; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D019703:Calcineurin