Computational Analysis Reveals a Key Regulator of Cryptococcal Virulence and Determinant of Host Response

ABSTRACT Cryptococcus neoformans is a ubiquitous, opportunistic fungal pathogen that kills over 600,000 people annually. Here, we report integrated computational and experimental investigations of the role and mechanisms of transcriptional regulation in cryptococcal infection. Major cryptococcal vir...

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Autores principales:	Stacey R. Gish, Ezekiel J. Maier, Brian C. Haynes, Felipe H. Santiago-Tirado, Deepa L. Srikanta, Cynthia Z. Ma, Lucy X. Li, Matthew Williams, Erika C. Crouch, Shabaana A. Khader, Michael R. Brent, Tamara L. Doering
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d87a9ac21823494f9eabd63ca287c8ad
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spelling	oai:doaj.org-article:d87a9ac21823494f9eabd63ca287c8ad2021-11-15T15:41:41ZComputational Analysis Reveals a Key Regulator of Cryptococcal Virulence and Determinant of Host Response10.1128/mBio.00313-162150-7511https://doaj.org/article/d87a9ac21823494f9eabd63ca287c8ad2016-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00313-16https://doaj.org/toc/2150-7511ABSTRACT Cryptococcus neoformans is a ubiquitous, opportunistic fungal pathogen that kills over 600,000 people annually. Here, we report integrated computational and experimental investigations of the role and mechanisms of transcriptional regulation in cryptococcal infection. Major cryptococcal virulence traits include melanin production and the development of a large polysaccharide capsule upon host entry; shed capsule polysaccharides also impair host defenses. We found that both transcription and translation are required for capsule growth and that Usv101 is a master regulator of pathogenesis, regulating melanin production, capsule growth, and capsule shedding. It does this by directly regulating genes encoding glycoactive enzymes and genes encoding three other transcription factors that are essential for capsule growth: GAT201, RIM101, and SP1. Murine infection with cryptococci lacking Usv101 significantly alters the kinetics and pathogenesis of disease, with extended survival and, unexpectedly, death by pneumonia rather than meningitis. Our approaches and findings will inform studies of other pathogenic microbes. IMPORTANCE Cryptococcus neoformans causes fatal meningitis in immunocompromised individuals, mainly HIV positive, killing over 600,000 each year. A unique feature of this yeast, which makes it particularly virulent, is its polysaccharide capsule; this structure impedes host efforts to combat infection. Capsule size and structure respond to environmental conditions, such as those encountered in an infected host. We have combined computational and experimental tools to elucidate capsule regulation, which we show primarily occurs at the transcriptional level. We also demonstrate that loss of a novel transcription factor alters virulence factor expression and host cell interactions, changing the lethal condition from meningitis to pneumonia with an exacerbated host response. We further demonstrate the relevant targets of regulation and kinetically map key regulatory and host interactions. Our work elucidates mechanisms of capsule regulation, provides methods and resources to the research community, and demonstrates an altered pathogenic outcome that resembles some human conditions.Stacey R. GishEzekiel J. MaierBrian C. HaynesFelipe H. Santiago-TiradoDeepa L. SrikantaCynthia Z. MaLucy X. LiMatthew WilliamsErika C. CrouchShabaana A. KhaderMichael R. BrentTamara L. DoeringAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 2 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Stacey R. Gish Ezekiel J. Maier Brian C. Haynes Felipe H. Santiago-Tirado Deepa L. Srikanta Cynthia Z. Ma Lucy X. Li Matthew Williams Erika C. Crouch Shabaana A. Khader Michael R. Brent Tamara L. Doering Computational Analysis Reveals a Key Regulator of Cryptococcal Virulence and Determinant of Host Response
description	ABSTRACT Cryptococcus neoformans is a ubiquitous, opportunistic fungal pathogen that kills over 600,000 people annually. Here, we report integrated computational and experimental investigations of the role and mechanisms of transcriptional regulation in cryptococcal infection. Major cryptococcal virulence traits include melanin production and the development of a large polysaccharide capsule upon host entry; shed capsule polysaccharides also impair host defenses. We found that both transcription and translation are required for capsule growth and that Usv101 is a master regulator of pathogenesis, regulating melanin production, capsule growth, and capsule shedding. It does this by directly regulating genes encoding glycoactive enzymes and genes encoding three other transcription factors that are essential for capsule growth: GAT201, RIM101, and SP1. Murine infection with cryptococci lacking Usv101 significantly alters the kinetics and pathogenesis of disease, with extended survival and, unexpectedly, death by pneumonia rather than meningitis. Our approaches and findings will inform studies of other pathogenic microbes. IMPORTANCE Cryptococcus neoformans causes fatal meningitis in immunocompromised individuals, mainly HIV positive, killing over 600,000 each year. A unique feature of this yeast, which makes it particularly virulent, is its polysaccharide capsule; this structure impedes host efforts to combat infection. Capsule size and structure respond to environmental conditions, such as those encountered in an infected host. We have combined computational and experimental tools to elucidate capsule regulation, which we show primarily occurs at the transcriptional level. We also demonstrate that loss of a novel transcription factor alters virulence factor expression and host cell interactions, changing the lethal condition from meningitis to pneumonia with an exacerbated host response. We further demonstrate the relevant targets of regulation and kinetically map key regulatory and host interactions. Our work elucidates mechanisms of capsule regulation, provides methods and resources to the research community, and demonstrates an altered pathogenic outcome that resembles some human conditions.
format	article
author	Stacey R. Gish Ezekiel J. Maier Brian C. Haynes Felipe H. Santiago-Tirado Deepa L. Srikanta Cynthia Z. Ma Lucy X. Li Matthew Williams Erika C. Crouch Shabaana A. Khader Michael R. Brent Tamara L. Doering
author_facet	Stacey R. Gish Ezekiel J. Maier Brian C. Haynes Felipe H. Santiago-Tirado Deepa L. Srikanta Cynthia Z. Ma Lucy X. Li Matthew Williams Erika C. Crouch Shabaana A. Khader Michael R. Brent Tamara L. Doering
author_sort	Stacey R. Gish
title	Computational Analysis Reveals a Key Regulator of Cryptococcal Virulence and Determinant of Host Response
title_short	Computational Analysis Reveals a Key Regulator of Cryptococcal Virulence and Determinant of Host Response
title_full	Computational Analysis Reveals a Key Regulator of Cryptococcal Virulence and Determinant of Host Response
title_fullStr	Computational Analysis Reveals a Key Regulator of Cryptococcal Virulence and Determinant of Host Response
title_full_unstemmed	Computational Analysis Reveals a Key Regulator of Cryptococcal Virulence and Determinant of Host Response
title_sort	computational analysis reveals a key regulator of cryptococcal virulence and determinant of host response
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/d87a9ac21823494f9eabd63ca287c8ad
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Computational Analysis Reveals a Key Regulator of Cryptococcal Virulence and Determinant of Host Response

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