<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Requires a Functional Glycolytic Pathway for Disease but Not Persistence in the Host

ABSTRACT Cryptococcus neoformans is an important fungal pathogen of immunocompromised individuals, with a close relative, Cryptococcus gattii, emerging as a serious threat for the immunocompetent. During initial infection, C. neoformans colonizes the airspaces of the lungs, resulting in pneumonia, a...

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Autores principales:	Michael S. Price, Marisol Betancourt-Quiroz, Jennifer L. Price, Dena L. Toffaletti, Haily Vora, Guanggan Hu, James W. Kronstad, John R. Perfect
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2011
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/dbe1734b88b84944aa7fc782c0731eeb
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spelling	oai:doaj.org-article:dbe1734b88b84944aa7fc782c0731eeb2021-11-15T15:38:49Z<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Requires a Functional Glycolytic Pathway for Disease but Not Persistence in the Host10.1128/mBio.00103-112150-7511https://doaj.org/article/dbe1734b88b84944aa7fc782c0731eeb2011-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00103-11https://doaj.org/toc/2150-7511ABSTRACT Cryptococcus neoformans is an important fungal pathogen of immunocompromised individuals, with a close relative, Cryptococcus gattii, emerging as a serious threat for the immunocompetent. During initial infection, C. neoformans colonizes the airspaces of the lungs, resulting in pneumonia, and subsequently migrates to the central nervous system (CNS). We sought to understand fungal carbon utilization during colonization of these fundamentally different niches within the host, in particular the roles of gluconeogenesis and glycolysis. We created mutants at key points in the gluconeogenesis/glycolysis metabolic pathways that are restricted for growth on lactate and glucose, respectively. A phosphoenolpyruvate carboxykinase mutant (the pck1∆ mutant), blocked for entry of 2- and 3-carbon substrates into gluconeogenesis and attenuated for virulence in a murine inhalation model, showed wild-type (WT) persistence in a rabbit cerebrospinal fluid (CSF) model of cryptococcosis. Conversely, both the pyruvate kinase (pyk1∆) and the hexose kinase I and II (hxk1∆/hxk2∆) mutants, which show impaired glucose utilization, exhibited severely attenuated virulence in the murine inhalation model of cryptococcosis and decreased persistence in the CNS in both the rabbit CSF and the murine inhalation models while displaying adequate persistence in the lungs of mice. These data suggest that glucose utilization is critical for virulence of C. neoformans and persistence of the yeast in the CNS. IMPORTANCE Cryptococcus neoformans is an emerging fungal pathogen of humans and is responsible for approximately 625,000 deaths annually among those suffering from HIV infection/AIDS. The ability of this fungus to persist in the host, coupled with its propensity to colonize the CNS, makes the understanding of nutrient acquisition in the host a primary concern. In this study, we report a requirement of glucose utilization for virulence of C. neoformans that is separate from its role in ATP production in the pathogen. Furthermore, we show that inhibition of glycolysis is a viable antifungal drug target, and impaired ATP production via the PYK1 deletion may serve as a model for dormant/chronic fungal infection in the host. Taken together, these results demonstrate the critical importance of understanding basic metabolic processes of the fungus in the context of host-pathogen interactions.Michael S. PriceMarisol Betancourt-QuirozJennifer L. PriceDena L. ToffalettiHaily VoraGuanggan HuJames W. KronstadJohn R. PerfectAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 2, Iss 3 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Michael S. Price Marisol Betancourt-Quiroz Jennifer L. Price Dena L. Toffaletti Haily Vora Guanggan Hu James W. Kronstad John R. Perfect <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Requires a Functional Glycolytic Pathway for Disease but Not Persistence in the Host
description	ABSTRACT Cryptococcus neoformans is an important fungal pathogen of immunocompromised individuals, with a close relative, Cryptococcus gattii, emerging as a serious threat for the immunocompetent. During initial infection, C. neoformans colonizes the airspaces of the lungs, resulting in pneumonia, and subsequently migrates to the central nervous system (CNS). We sought to understand fungal carbon utilization during colonization of these fundamentally different niches within the host, in particular the roles of gluconeogenesis and glycolysis. We created mutants at key points in the gluconeogenesis/glycolysis metabolic pathways that are restricted for growth on lactate and glucose, respectively. A phosphoenolpyruvate carboxykinase mutant (the pck1∆ mutant), blocked for entry of 2- and 3-carbon substrates into gluconeogenesis and attenuated for virulence in a murine inhalation model, showed wild-type (WT) persistence in a rabbit cerebrospinal fluid (CSF) model of cryptococcosis. Conversely, both the pyruvate kinase (pyk1∆) and the hexose kinase I and II (hxk1∆/hxk2∆) mutants, which show impaired glucose utilization, exhibited severely attenuated virulence in the murine inhalation model of cryptococcosis and decreased persistence in the CNS in both the rabbit CSF and the murine inhalation models while displaying adequate persistence in the lungs of mice. These data suggest that glucose utilization is critical for virulence of C. neoformans and persistence of the yeast in the CNS. IMPORTANCE Cryptococcus neoformans is an emerging fungal pathogen of humans and is responsible for approximately 625,000 deaths annually among those suffering from HIV infection/AIDS. The ability of this fungus to persist in the host, coupled with its propensity to colonize the CNS, makes the understanding of nutrient acquisition in the host a primary concern. In this study, we report a requirement of glucose utilization for virulence of C. neoformans that is separate from its role in ATP production in the pathogen. Furthermore, we show that inhibition of glycolysis is a viable antifungal drug target, and impaired ATP production via the PYK1 deletion may serve as a model for dormant/chronic fungal infection in the host. Taken together, these results demonstrate the critical importance of understanding basic metabolic processes of the fungus in the context of host-pathogen interactions.
format	article
author	Michael S. Price Marisol Betancourt-Quiroz Jennifer L. Price Dena L. Toffaletti Haily Vora Guanggan Hu James W. Kronstad John R. Perfect
author_facet	Michael S. Price Marisol Betancourt-Quiroz Jennifer L. Price Dena L. Toffaletti Haily Vora Guanggan Hu James W. Kronstad John R. Perfect
author_sort	Michael S. Price
title	<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Requires a Functional Glycolytic Pathway for Disease but Not Persistence in the Host
title_short	<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Requires a Functional Glycolytic Pathway for Disease but Not Persistence in the Host
title_full	<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Requires a Functional Glycolytic Pathway for Disease but Not Persistence in the Host
title_fullStr	<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Requires a Functional Glycolytic Pathway for Disease but Not Persistence in the Host
title_full_unstemmed	<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Requires a Functional Glycolytic Pathway for Disease but Not Persistence in the Host
title_sort	<named-content content-type="genus-species">cryptococcus neoformans</named-content> requires a functional glycolytic pathway for disease but not persistence in the host
publisher	American Society for Microbiology
publishDate	2011
url	https://doaj.org/article/dbe1734b88b84944aa7fc782c0731eeb
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<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Requires a Functional Glycolytic Pathway for Disease but Not Persistence in the Host

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