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Transcriptional Regulation of Chitin Synthases by Calcineurin Controls Paradoxical Growth of Aspergillus fumigatus in Response to Caspofungin
Open accessAbstract
Attenuated activity of echinocandin antifungals at high concentrations, known as the “paradoxical effect,” is a well-established phenomenon in Candida albicans and Aspergillus fumigatus . In the yeast C. albicans , upregulation of chitin biosynthesis via the protein kinase C (PKC), high-osmolarity glycerol response (HOG), and Ca 2+ /calcineurin signaling pathways is an important cell wall stress response that permits growth in the presence of high concentrations of echinocandins. However, nothing is known of the molecular mechanisms regulating the mold A. fumigatus and its paradoxical response to echinocandins. Here, we show that the laboratory strain of A. fumigatus and five of seven clinical A. fumigatus isolates tested display various magnitudes of paradoxical growth in response to caspofungin. Interestingly, none of the eight strains showed paradoxical growth in the presence of micafungin or anidulafungin. Treatment of the Δ cnaA and Δ crzA strains, harboring gene deletions of the calcineurin A subunit and the calcineurin-dependent transcription factor, respectively, with high concentrations of caspofungin revealed that the A. fumigatus paradoxical effect is calcineurin pathway dependent. Exploring a molecular role for CnaA in the compensatory chitin biosynthetic response, we found that caspofungin treatment resulted in increased chitin synthase gene expression, leading to a calcineurin-dependent increase in chitin synthase activity. Taken together, our data suggest a mechanistic role for A. fumigatus calcineurin signaling in the chitin biosynthetic response observed during paradoxical growth in the presence of high-dose caspofungin treatment.
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In the citing paper
“As calcineurin also increases echinocandin tolerance in C. albicans and A. fumigatus (45, 46)”
From Echinocandin tolerance and persistence in vitro are regulated by calcineurin signaling in Candida glabrata (2026) · cites this paper as [46]
In the citing paper
“For A. fumigatus, the chitin biosynthetic response is controlled, at least in part, by calcineurin-mediated transcriptional upregulation of chitin synthases83.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [83]
In the citing paper
“Genetic or pharmacologic repression of Hsp90 resulted in various similar phenotypic consequences compared to calcineurin deletion, such as impaired hyphal elongation, decreased β-glucan content of the cell wall, defective sporulation, and increased susceptibility to caspofungin with abolition of the paradoxical effect of this drug”
From Calcineurin as a multifunctional regulator: Unraveling novel functions in fungal stress responses, hyphal growth, drug resistance, and pathogenesis (2014) · cites this paper as Fortwendel et al., 2010
In the citing paper
“Genetic or pharmacologic repression of Hsp90 resulted in various similar phenotypic consequences compared to calcineurin deletion, such as impaired hyphal elongation, decreased β-glucan content of the cell wall, defective sporulation, and increased susceptibility to caspofungin with abolition of the paradoxical effect of this drug”
From Calcineurin as a multifunctional regulator: Unraveling novel functions in fungal stress responses, hyphal growth, drug resistance, and pathogenesis (2014) · cites this paper as Fortwendel et al., 2010
In the citing paper
“Genetic or pharmacologic repression of Hsp90 resulted in various similar phenotypic consequences compared to calcineurin deletion, such as impaired hyphal elongation, decreased β-glucan content of the cell wall, defective sporulation, and increased susceptibility to caspofungin with abolition of the paradoxical effect of this drug”
From Calcineurin as a multifunctional regulator: Unraveling novel functions in fungal stress responses, hyphal growth, drug resistance, and pathogenesis (2014) · cites this paper as Fortwendel et al., 2010
In the citing paper
“Genetic or pharmacologic repression of Hsp90 resulted in various similar phenotypic consequences compared to calcineurin deletion, such as impaired hyphal elongation, decreased β-glucan content of the cell wall, defective sporulation, and increased susceptibility to caspofungin with abolition of the paradoxical effect of this drug”
From Calcineurin as a multifunctional regulator: Unraveling novel functions in fungal stress responses, hyphal growth, drug resistance, and pathogenesis (2014) · cites this paper as Fortwendel et al., 2010
In the citing paper
“Akin to the Hsp90 repression strain, the A. fumigatus ΔcrzA strain exhibited the same sporulation and cell wall defects, and was also hypersensitive to caspofungin and incapable of generating a paradoxical response at high caspofungin concentrations (Cramer et al., 2008; Fortwendel et al., 2010; Fortwendel et al., 2009).”
From Calcineurin as a multifunctional regulator: Unraveling novel functions in fungal stress responses, hyphal growth, drug resistance, and pathogenesis (2014) · cites this paper as Fortwendel et al., 2010
In the citing paper
“Akin to the Hsp90 repression strain, the A. fumigatus ΔcrzA strain exhibited the same sporulation and cell wall defects, and was also hypersensitive to caspofungin and incapable of generating a paradoxical response at high caspofungin concentrations (Cramer et al., 2008; Fortwendel et al., 2010; Fortwendel et al., 2009).”
From Calcineurin as a multifunctional regulator: Unraveling novel functions in fungal stress responses, hyphal growth, drug resistance, and pathogenesis (2014) · cites this paper as Fortwendel et al., 2010
In the citing paper
“Akin to the Hsp90 repression strain, the A. fumigatus ΔcrzA strain exhibited the same sporulation and cell wall defects, and was also hypersensitive to caspofungin and incapable of generating a paradoxical response at high caspofungin concentrations (Cramer et al., 2008; Fortwendel et al., 2010; Fortwendel et al., 2009).”
From Calcineurin as a multifunctional regulator: Unraveling novel functions in fungal stress responses, hyphal growth, drug resistance, and pathogenesis (2014) · cites this paper as Fortwendel et al., 2010
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Citations
Cites
Stimulation of Chitin Synthesis Rescues Candida albicans from Echinocandins
Walker, L. A., Munro, C. A., de Bruijn, I., Lenardon, M. D., McKinnon, A., & Gow, N. A. R. (2008) · PLoS Pathogens · doi:10.1371/journal.ppat.1000040 · Cited by 445
Yoshimoto, H., Saltsman, K., Gasch, A. P., Li, H. X., Ogawa, N., Botstein, D., Brown, P. O., & Cyert, M. S. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202718200 · Cited by 404
Liu, T. T., Lee, R. E. B., Barker, K. S., Lee, R. E., Wei, L., Homayouni, R., & Rogers, P. D. (2005) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.49.6.2226-2236.2005 · Cited by 313
Munro, C. A., Selvaggini, S., De Bruijn, I., Walker, L., Lenardon, M. D., Gerssen, B., Milne, S., Brown, A. J. P., & Gow, N. A. R. (2007) · Molecular Microbiology · doi:10.1111/j.1365-2958.2007.05588.x · Cited by 309
Calcineurin Controls Growth, Morphology, and Pathogenicity in Aspergillus fumigatus
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., et al. (2006) · Eukaryotic Cell · doi:10.1128/ec.00139-06 · Cited by 264
Self-citationCalcineurin and mitochondrial function in glutamate‐induced neuronal cell death
Ankarcrona, M., Dypbukt, J. M., Orrenius, S., & Nicotera, P. (1996) · FEBS Letters · doi:10.1016/0014-5793(96)00959-3 · Cited by 227
Stevens, D. A., Espiritu, M., & Parmar, R. (2004) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.48.9.3407-3411.2004 · Cited by 218
Wiederhold, N. P., Kontoyiannis, D. P., Chi, J., Prince, R. A., Tam, V. H., & Lewis, R. E. (2004) · The Journal of Infectious Diseases · doi:10.1086/424465 · Cited by 206
Agarwal, A. K., Rogers, P. D., Baerson, S. R., Jacob, M. R., Barker, K. S., Cleary, J. D., Walker, L. A., Nagle, D. G., & Clark, A. M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m306291200 · Cited by 204
Stevens, D. A., Ichinomiya, M., Koshi, Y., & Horiuchi, H. (2006) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00563-06 · Cited by 193
Cited by
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Regulatory circuitry governing fungal development, drug resistance, and disease.
Shapiro, R. S., Robbins, N., & Cowen, L. E. (2011) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00045-10 · Cited by 576
Chitin synthesis and fungal pathogenesis
Lenardon, M. D., Munro, C. A., & Gow, N. A. (2010) · Current Opinion in Microbiology · doi:10.1016/j.mib.2010.05.002 · Cited by 502
Molecular mechanisms governing antifungal drug resistance
Lee, Y., Robbins, N., & Cowen, L. E. (2023) · npj Antimicrobials and Resistance · doi:10.1038/s44259-023-00007-2 · Cited by 304
New Horizons in Antifungal Therapy
Pianalto, K. M., & Alspaugh, J. A. (2016) · Journal of Fungi · doi:10.3390/jof2040026 · Cited by 197
Valiante, V., Macheleidt, J., Föge, M., & Brakhage, A. A. (2015) · Frontiers in Microbiology · doi:10.3389/fmicb.2015.00325 · Cited by 189
Metadata
- Authors
- Fortwendel, J. R., Juvvadi, P. R., Perfect, B. Z., Rogg, L. E., Perfect, J. R., & Steinbach, W. J.
- Affiliations
- Departments of Pediatrics
- Duke Medical Center (US)
- Corresponding author
- Steinbach, William J.
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2010-04
- Volume
- 54
- Issue
- 4
- Pages
- 1555-1563
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC2849361
- OpenAlex
- W2126957470
- Cited by
- 153
- References
- 39
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 8 · 2023: 9 · 2022: 9 · 2021: 8 · 2020: 18 · 2019: 12 · 2018: 4 · 2017: 13 · 2016: 11 · 2015: 10 · 2014: 13 · 2013: 6 · 2012: 7
- FWCI
- 3.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Children's Miracle Network Hospitals
- Astellas Pharma
- U.S. Public Health Service (A1061149)
- National Institute of Allergy and Infectious Diseases (T32AI052080)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Infectious Diseases › Fungal Infections and Studies
- Keywords
- Aspergillus fumigatus, caspofungin, echinocandins, calcineurin signaling, chitin synthase, chitin synthesis, transcriptional regulation, antifungal resistance, cell wall stress response, micafungin, anidulafungin
- MeSH terms
- Caspofungin, Antifungal Agents, Aspergillus fumigatus, Base Sequence, Chitin Synthase, DNA, Fungal, Fungal Proteins, Genes, Fungal, Transcription Factors, Signal Transduction, Gene Expression Regulation, Fungal, Gene Deletion, DNA Primers, Calcineurin, Echinocandins, Lipopeptides
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