Reducing <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Virulence through Targeted Dysregulation of the Conidiation Pathway

ABSTRACT Inhalation of conidia of the opportunistic mold Aspergillus fumigatus by immunocompromised hosts can lead to invasive pulmonary disease. Inhaled conidia that escape immune defenses germinate to form filamentous hyphae that invade lung tissues. Conidiation rarely occurs during invasive infec...

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Autores principales:	James I. P. Stewart, Vinicius M. Fava, Joshua D. Kerkaert, Adithya S. Subramanian, Fabrice N. Gravelat, Melanie Lehoux, P. Lynne Howell, Robert A. Cramer, Donald C. Sheppard
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Aspergillus fumigatus RNA sequencing conidiation drug targets inducible gene expression opportunistic pathogen Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9ce0b03a0eff449bb4e6cf7bbbc2a825
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spelling	oai:doaj.org-article:9ce0b03a0eff449bb4e6cf7bbbc2a8252021-11-15T15:56:58ZReducing <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Virulence through Targeted Dysregulation of the Conidiation Pathway10.1128/mBio.03202-192150-7511https://doaj.org/article/9ce0b03a0eff449bb4e6cf7bbbc2a8252020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03202-19https://doaj.org/toc/2150-7511ABSTRACT Inhalation of conidia of the opportunistic mold Aspergillus fumigatus by immunocompromised hosts can lead to invasive pulmonary disease. Inhaled conidia that escape immune defenses germinate to form filamentous hyphae that invade lung tissues. Conidiation rarely occurs during invasive infection of the human host, allowing the bulk of fungal energy to be directed toward vegetative growth. We hypothesized that forced induction of conidiation during infection can suppress A. fumigatus vegetative growth, impairing the ability of this organism to cause disease. To study the effects of conidiation pathway dysregulation on A. fumigatus virulence, a key transcriptional regulator of conidiation (brlA) was expressed under the control of a doxycycline-inducible promoter. Time- and dose-dependent brlA overexpression was observed in response to doxycycline both in vitro and in vivo. Exposure of the inducible brlA overexpression strain to low doses of doxycycline under vegetative growth conditions in vitro induced conidiation, whereas high doses arrested growth. Overexpression of brlA attenuated A. fumigatus virulence in both an invertebrate and mouse model of invasive aspergillosis. RNA sequencing studies and phenotypic analysis revealed that brlA overexpression results in altered cell signaling, amino acid, and carbohydrate metabolism, including a marked upregulation of trehalose biosynthesis and a downregulation in the biosynthesis of the polysaccharide virulence factor galactosaminogalactan. This proof of concept study demonstrates that activation of the conidiation pathway in A. fumigatus can reduce virulence and suggests that brlA-inducing small molecules may hold promise as a new class of therapeutics for A. fumigatus infection. IMPORTANCE The mold Aspergillus fumigatus reproduces by the production of airborne spores (conidia), a process termed conidiation. In immunocompromised individuals, inhaled A. fumigatus conidia can germinate and form filaments that penetrate and damage lung tissues; however, conidiation does not occur during invasive infection. In this study, we demonstrate that forced activation of conidiation in filaments of A. fumigatus can arrest their growth and impair the ability of this fungus to cause disease in both an insect and a mouse model of invasive infection. Activation of conidiation was linked to profound changes in A. fumigatus metabolism, including a shift away from the synthesis of polysaccharides required for cell wall structure and virulence in favor of carbohydrates used for energy storage and stress resistance. Collectively, these findings suggest that activation of the conidiation pathway may be a promising approach for the development of new agents to prevent or treat A. fumigatus infection.James I. P. StewartVinicius M. FavaJoshua D. KerkaertAdithya S. SubramanianFabrice N. GravelatMelanie LehouxP. Lynne HowellRobert A. CramerDonald C. SheppardAmerican Society for MicrobiologyarticleAspergillus fumigatusRNA sequencingconidiationdrug targetsinducible gene expressionopportunistic pathogenMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Aspergillus fumigatus RNA sequencing conidiation drug targets inducible gene expression opportunistic pathogen Microbiology QR1-502
spellingShingle	Aspergillus fumigatus RNA sequencing conidiation drug targets inducible gene expression opportunistic pathogen Microbiology QR1-502 James I. P. Stewart Vinicius M. Fava Joshua D. Kerkaert Adithya S. Subramanian Fabrice N. Gravelat Melanie Lehoux P. Lynne Howell Robert A. Cramer Donald C. Sheppard Reducing <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Virulence through Targeted Dysregulation of the Conidiation Pathway
description	ABSTRACT Inhalation of conidia of the opportunistic mold Aspergillus fumigatus by immunocompromised hosts can lead to invasive pulmonary disease. Inhaled conidia that escape immune defenses germinate to form filamentous hyphae that invade lung tissues. Conidiation rarely occurs during invasive infection of the human host, allowing the bulk of fungal energy to be directed toward vegetative growth. We hypothesized that forced induction of conidiation during infection can suppress A. fumigatus vegetative growth, impairing the ability of this organism to cause disease. To study the effects of conidiation pathway dysregulation on A. fumigatus virulence, a key transcriptional regulator of conidiation (brlA) was expressed under the control of a doxycycline-inducible promoter. Time- and dose-dependent brlA overexpression was observed in response to doxycycline both in vitro and in vivo. Exposure of the inducible brlA overexpression strain to low doses of doxycycline under vegetative growth conditions in vitro induced conidiation, whereas high doses arrested growth. Overexpression of brlA attenuated A. fumigatus virulence in both an invertebrate and mouse model of invasive aspergillosis. RNA sequencing studies and phenotypic analysis revealed that brlA overexpression results in altered cell signaling, amino acid, and carbohydrate metabolism, including a marked upregulation of trehalose biosynthesis and a downregulation in the biosynthesis of the polysaccharide virulence factor galactosaminogalactan. This proof of concept study demonstrates that activation of the conidiation pathway in A. fumigatus can reduce virulence and suggests that brlA-inducing small molecules may hold promise as a new class of therapeutics for A. fumigatus infection. IMPORTANCE The mold Aspergillus fumigatus reproduces by the production of airborne spores (conidia), a process termed conidiation. In immunocompromised individuals, inhaled A. fumigatus conidia can germinate and form filaments that penetrate and damage lung tissues; however, conidiation does not occur during invasive infection. In this study, we demonstrate that forced activation of conidiation in filaments of A. fumigatus can arrest their growth and impair the ability of this fungus to cause disease in both an insect and a mouse model of invasive infection. Activation of conidiation was linked to profound changes in A. fumigatus metabolism, including a shift away from the synthesis of polysaccharides required for cell wall structure and virulence in favor of carbohydrates used for energy storage and stress resistance. Collectively, these findings suggest that activation of the conidiation pathway may be a promising approach for the development of new agents to prevent or treat A. fumigatus infection.
format	article
author	James I. P. Stewart Vinicius M. Fava Joshua D. Kerkaert Adithya S. Subramanian Fabrice N. Gravelat Melanie Lehoux P. Lynne Howell Robert A. Cramer Donald C. Sheppard
author_facet	James I. P. Stewart Vinicius M. Fava Joshua D. Kerkaert Adithya S. Subramanian Fabrice N. Gravelat Melanie Lehoux P. Lynne Howell Robert A. Cramer Donald C. Sheppard
author_sort	James I. P. Stewart
title	Reducing <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Virulence through Targeted Dysregulation of the Conidiation Pathway
title_short	Reducing <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Virulence through Targeted Dysregulation of the Conidiation Pathway
title_full	Reducing <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Virulence through Targeted Dysregulation of the Conidiation Pathway
title_fullStr	Reducing <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Virulence through Targeted Dysregulation of the Conidiation Pathway
title_full_unstemmed	Reducing <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Virulence through Targeted Dysregulation of the Conidiation Pathway
title_sort	reducing <named-content content-type="genus-species">aspergillus fumigatus</named-content> virulence through targeted dysregulation of the conidiation pathway
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/9ce0b03a0eff449bb4e6cf7bbbc2a825
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Reducing <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Virulence through Targeted Dysregulation of the Conidiation Pathway

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