Tornadic Shear Stress Induces a Transient, Calcineurin-Dependent Hypervirulent Phenotype in Mucorales Molds
ABSTRACT Trauma-related necrotizing myocutaneous mucormycosis (NMM) has a high morbidity and mortality in victims of combat-related injuries, geometeorological disasters, and severe burns. Inspired by the observation that several recent clusters of NMM have been associated with extreme mechanical fo...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2020-06-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.01414-20 |
| _version_ | 1818900640135380992 |
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| author | Sebastian Wurster Alexander M. Tatara Nathaniel D. Albert Ashraf S. Ibrahim Joseph Heitman Soo Chan Lee Amol C. Shetty Carrie McCracken Karen T. Graf Antonios G. Mikos Vincent M. Bruno Dimitrios P. Kontoyiannis |
| author_facet | Sebastian Wurster Alexander M. Tatara Nathaniel D. Albert Ashraf S. Ibrahim Joseph Heitman Soo Chan Lee Amol C. Shetty Carrie McCracken Karen T. Graf Antonios G. Mikos Vincent M. Bruno Dimitrios P. Kontoyiannis |
| author_sort | Sebastian Wurster |
| collection | DOAJ |
| description | ABSTRACT Trauma-related necrotizing myocutaneous mucormycosis (NMM) has a high morbidity and mortality in victims of combat-related injuries, geometeorological disasters, and severe burns. Inspired by the observation that several recent clusters of NMM have been associated with extreme mechanical forces (e.g., during tornados), we studied the impact of mechanical stress on Mucoralean biology and virulence in a Drosophila melanogaster infection model. In contrast to other experimental procedures to exert mechanical stress, tornadic shear challenge (TSC) by magnetic stirring induced a hypervirulent phenotype in several clinically relevant Mucorales species but not in Aspergillus or Fusarium. Whereas fungal growth rates, morphogenesis, and susceptibility to noxious environments or phagocytes were not altered by TSC, soluble factors released in the supernatant of shear-challenged R. arrhizus spores rendered static spores hypervirulent. Consistent with a rapid decay of TSC-induced hypervirulence, minimal transcriptional changes were revealed by comparative RNA sequencing analysis of static and shear-challenged Rhizopus arrhizus. However, inhibition of the calcineurin/heat shock protein 90 (hsp90) stress response circuitry by cyclosporine and tanespimycin abrogated the increased pathogenicity of R. arrhizus spores following TSC. Similarly, calcineurin loss-of-function mutants of Mucor circinelloides displayed no increased virulence capacity in flies after undergoing TSC. Collectively, these results establish that TSC induces hypervirulence specifically in Mucorales and point out the calcineurin/hsp90 pathway as a key orchestrator of this phenotype. Our findings invite future studies of topical calcineurin inhibitor treatment of wounds as an adjunct mitigation strategy for NMM following high-energy trauma. IMPORTANCE Given the limited efficacy of current medical treatments in trauma-related necrotizing mucormycosis, there is a dire need to better understand the Mucoralean pathophysiology in order to develop novel strategies to counteract fungal tissue invasion following severe trauma. Here, we describe that tornadic shear stress challenge transiently induces a hypervirulent phenotype in various pathogenic Mucorales species but not in other molds known to cause wound infections. Pharmacological and genetic inhibition of calcineurin signaling abrogated hypervirulence in shear stress-challenged Mucorales, encouraging further evaluation of (topical) calcineurin inhibitors to improve therapeutic outcomes of NMM after combat-related blast injuries or violent storms. |
| first_indexed | 2024-12-19T20:07:04Z |
| format | Article |
| id | doaj.art-1d82ac74355b42f0895c16fb72c03309 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-19T20:07:04Z |
| publishDate | 2020-06-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-1d82ac74355b42f0895c16fb72c033092022-12-21T20:07:26ZengAmerican Society for MicrobiologymBio2150-75112020-06-0111310.1128/mBio.01414-20Tornadic Shear Stress Induces a Transient, Calcineurin-Dependent Hypervirulent Phenotype in Mucorales MoldsSebastian Wurster0Alexander M. Tatara1Nathaniel D. Albert2Ashraf S. Ibrahim3Joseph Heitman4Soo Chan Lee5Amol C. Shetty6Carrie McCracken7Karen T. Graf8Antonios G. Mikos9Vincent M. Bruno10Dimitrios P. Kontoyiannis11Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USADepartment of Bioengineering, Rice University, Houston, Texas, USADepartment of Infectious Diseases, Infection Control and Employee Health, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USALos Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Los Angeles, California, USADepartments of Molecular Genetics and Microbiology, Pharmacology and Cancer Biology, and Medicine, Duke University Medical Center, Durham, North Carolina, USASouth Texas Center of Emerging Infectious Diseases, Department of Biology, University of Texas at San Antonio, San Antonio, Texas, USAThe Institute for Genome Sciences, University of Maryland, Baltimore, Maryland, USAThe Institute for Genome Sciences, University of Maryland, Baltimore, Maryland, USAThe Institute for Genome Sciences, University of Maryland, Baltimore, Maryland, USADepartment of Bioengineering, Rice University, Houston, Texas, USAThe Institute for Genome Sciences, University of Maryland, Baltimore, Maryland, USADepartment of Infectious Diseases, Infection Control and Employee Health, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USAABSTRACT Trauma-related necrotizing myocutaneous mucormycosis (NMM) has a high morbidity and mortality in victims of combat-related injuries, geometeorological disasters, and severe burns. Inspired by the observation that several recent clusters of NMM have been associated with extreme mechanical forces (e.g., during tornados), we studied the impact of mechanical stress on Mucoralean biology and virulence in a Drosophila melanogaster infection model. In contrast to other experimental procedures to exert mechanical stress, tornadic shear challenge (TSC) by magnetic stirring induced a hypervirulent phenotype in several clinically relevant Mucorales species but not in Aspergillus or Fusarium. Whereas fungal growth rates, morphogenesis, and susceptibility to noxious environments or phagocytes were not altered by TSC, soluble factors released in the supernatant of shear-challenged R. arrhizus spores rendered static spores hypervirulent. Consistent with a rapid decay of TSC-induced hypervirulence, minimal transcriptional changes were revealed by comparative RNA sequencing analysis of static and shear-challenged Rhizopus arrhizus. However, inhibition of the calcineurin/heat shock protein 90 (hsp90) stress response circuitry by cyclosporine and tanespimycin abrogated the increased pathogenicity of R. arrhizus spores following TSC. Similarly, calcineurin loss-of-function mutants of Mucor circinelloides displayed no increased virulence capacity in flies after undergoing TSC. Collectively, these results establish that TSC induces hypervirulence specifically in Mucorales and point out the calcineurin/hsp90 pathway as a key orchestrator of this phenotype. Our findings invite future studies of topical calcineurin inhibitor treatment of wounds as an adjunct mitigation strategy for NMM following high-energy trauma. IMPORTANCE Given the limited efficacy of current medical treatments in trauma-related necrotizing mucormycosis, there is a dire need to better understand the Mucoralean pathophysiology in order to develop novel strategies to counteract fungal tissue invasion following severe trauma. Here, we describe that tornadic shear stress challenge transiently induces a hypervirulent phenotype in various pathogenic Mucorales species but not in other molds known to cause wound infections. Pharmacological and genetic inhibition of calcineurin signaling abrogated hypervirulence in shear stress-challenged Mucorales, encouraging further evaluation of (topical) calcineurin inhibitors to improve therapeutic outcomes of NMM after combat-related blast injuries or violent storms.https://journals.asm.org/doi/10.1128/mBio.01414-20mucormycosisvirulencemechanobiologytraumastress response |
| spellingShingle | Sebastian Wurster Alexander M. Tatara Nathaniel D. Albert Ashraf S. Ibrahim Joseph Heitman Soo Chan Lee Amol C. Shetty Carrie McCracken Karen T. Graf Antonios G. Mikos Vincent M. Bruno Dimitrios P. Kontoyiannis Tornadic Shear Stress Induces a Transient, Calcineurin-Dependent Hypervirulent Phenotype in Mucorales Molds mBio mucormycosis virulence mechanobiology trauma stress response |
| title | Tornadic Shear Stress Induces a Transient, Calcineurin-Dependent Hypervirulent Phenotype in Mucorales Molds |
| title_full | Tornadic Shear Stress Induces a Transient, Calcineurin-Dependent Hypervirulent Phenotype in Mucorales Molds |
| title_fullStr | Tornadic Shear Stress Induces a Transient, Calcineurin-Dependent Hypervirulent Phenotype in Mucorales Molds |
| title_full_unstemmed | Tornadic Shear Stress Induces a Transient, Calcineurin-Dependent Hypervirulent Phenotype in Mucorales Molds |
| title_short | Tornadic Shear Stress Induces a Transient, Calcineurin-Dependent Hypervirulent Phenotype in Mucorales Molds |
| title_sort | tornadic shear stress induces a transient calcineurin dependent hypervirulent phenotype in mucorales molds |
| topic | mucormycosis virulence mechanobiology trauma stress response |
| url | https://journals.asm.org/doi/10.1128/mBio.01414-20 |
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