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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	mucormycosis virulence mechanobiology trauma stress response Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1d82ac74355b42f0895c16fb72c03309
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spelling	oai:doaj.org-article:1d82ac74355b42f0895c16fb72c033092021-11-15T15:56:46ZTornadic Shear Stress Induces a Transient, Calcineurin-Dependent Hypervirulent Phenotype in Mucorales Molds10.1128/mBio.01414-202150-7511https://doaj.org/article/1d82ac74355b42f0895c16fb72c033092020-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01414-20https://doaj.org/toc/2150-7511ABSTRACT 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.Sebastian WursterAlexander M. TataraNathaniel D. AlbertAshraf S. IbrahimJoseph HeitmanSoo Chan LeeAmol C. ShettyCarrie McCrackenKaren T. GrafAntonios G. MikosVincent M. BrunoDimitrios P. KontoyiannisAmerican Society for Microbiologyarticlemucormycosisvirulencemechanobiologytraumastress responseMicrobiologyQR1-502ENmBio, Vol 11, Iss 3 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	mucormycosis virulence mechanobiology trauma stress response Microbiology QR1-502
spellingShingle	mucormycosis virulence mechanobiology trauma stress response Microbiology QR1-502 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
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.
format	article
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
title	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_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_sort	tornadic shear stress induces a transient, calcineurin-dependent hypervirulent phenotype in mucorales molds
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/1d82ac74355b42f0895c16fb72c03309
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Tornadic Shear Stress Induces a Transient, Calcineurin-Dependent Hypervirulent Phenotype in Mucorales Molds

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