Calcineurin Controls Growth, Morphology, and Pathogenicity in Aspergillus fumigatus
Open accessAbstract
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 Δ cnaA mutant lacked the extensive lattice of invading hyphae seen with the wild-type and complemented strains. Sporulation was also affected in the Δ 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 Δ 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 Δ 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.
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The C. glabrata Δcnb1 strain phenotype (increased susceptibility to azoles and cell wall-damaging agents, decreased virulence) is consistent with previous findings for other pathogenic fungi.
“For example, the observed C. glabrata Δcnb1 strain phenotype, which is characterized by an increased susceptibility to azoles and cell wall-damaging agents as well as decreased virulence, is consistent with previous findings for other pathogenic fungi, such as C. albicans (2-4, 27), C. neoformans (11, 18, 21), and A. fumigatus (9, 30).”
From Roles of Calcineurin and Crz1 in Antifungal Susceptibility and Virulence of <i>Candida glabrata</i> (2010) · cites this paper as [30]
Calcineurin is not an essential gene in A. fumigatus, but it is a key phosphatase involved in regulating differentiation and fitness of this opportunistic pathogen.
“Though calcineurin is not an essential gene in A. fumigatus, it is a key phosphatase involved in regulating the differentiation and fitness of this opportunistic pathogen (Ferreira et al., 2007; Steinbach et al., 2006).”
From Calcineurin as a multifunctional regulator: Unraveling novel functions in fungal stress responses, hyphal growth, drug resistance, and pathogenesis (2014) · cites this paper as Steinbach et al., 2006
A. fumigatus lacking either the calcineurin catalytic subunit or the regulatory subunit exhibited defective hyphal morphology related to apical extension and branching.
“A. fumigatus lacking either the calcineurin catalytic subunit or the regulatory subunit exhibited defective hyphal morphology related to apical extension and branching (Juvvadi et al., 2011; Steinbach et al., 2006).”
From Calcineurin as a multifunctional regulator: Unraveling novel functions in fungal stress responses, hyphal growth, drug resistance, and pathogenesis (2014) · cites this paper as Steinbach et al., 2006
Calcineurin A and B subunits localize at the septum and play a key role in septum formation and cell wall integrity.
“These results suggest the possibility of Hsp90-calcineurin interactions under cell wall stress conditions, as both the calcineurin A and B subunits were shown to localize at the septum and to play a key role in septum formation and cell wall integrity (Juvvadi et al., 2011; Steinbach et al., 2006).”
From Calcineurin as a multifunctional regulator: Unraveling novel functions in fungal stress responses, hyphal growth, drug resistance, and pathogenesis (2014) · cites this paper as Steinbach et al., 2006
Hsp90-calcineurin interactions may occur under cell wall stress conditions.
“These results suggest the possibility of Hsp90-calcineurin interactions under cell wall stress conditions, as both the calcineurin A and B subunits were shown to localize at the septum and to play a key role in septum formation and cell wall integrity (Juvvadi et al., 2011; Steinbach et al., 2006).”
From Calcineurin as a multifunctional regulator: Unraveling novel functions in fungal stress responses, hyphal growth, drug resistance, and pathogenesis (2014) · cites this paper as Steinbach et al., 2006
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References 40 · Cited by 264
- Authors
- Steinbach, W. J., Cramer, R. A., Perfect, B. Z., Asfaw, Y. G., Sauer, T. C., Najvar, L. K., Kirkpatrick, W. R., Patterson, T. F., Benjamin, D. K., Heitman, J., & Perfect, J. R.
- Affiliations
- Department of Pediatrics
- Department of Molecular Genetics and Microbiology
- Department of Laboratory Animal Resources
- The University of Texas at San Antonio Health Science Center (US)
- Duke Medical Center (US)
- Corresponding author
- Steinbach, William J.
- ORCID
- Venue
- Eukaryotic Cell
- Publisher
- American Society for Microbiology
- Published
- 2006-07
- Volume
- 5
- Issue
- 7
- Pages
- 1091-1103
- ISSN
- 1535-9778 (ISSN-L)
- 1535-9786
- OpenAlex
- W2122653633
- Cited by
- 264
- References
- 40
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 3 · 2023: 7 · 2022: 7 · 2021: 9 · 2020: 16 · 2019: 11 · 2018: 12 · 2017: 15 · 2016: 19 · 2015: 18 · 2014: 27 · 2013: 17 · 2012: 13
- FWCI
- 9.45
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Locations
- Eukaryotic Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- National Institutes of Health
- U.S. Public Health Service (1 K08 A1061149)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Keywords
- calcineurin, Aspergillus fumigatus, invasive aspergillosis, fungal virulence, hyphal morphology, polarized growth, filamentation, sporulation, immunosuppression, antifungal drug targets, pulmonary infection
- MeSH terms
- Animals, Aspergillus fumigatus, Male, Mice, Inbred DBA, Mice, Inbred ICR, Morphogenesis, Mutation, Colony Count, Microbial, Sequence Deletion, Blood-Borne Pathogens, Calcineurin, Neuroaspergillosis, Mice
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