<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Cda1 and Its Chitin Deacetylase Activity Are Required for Fungal Pathogenesis

ABSTRACT Chitin is an essential component of the cell wall of Cryptococcus neoformans conferring structural rigidity and integrity under diverse environmental conditions. Chitin deacetylase genes encode the enyzmes (chitin deacetylases [Cdas]) that deacetylate chitin, converting it to chitosan. The...

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Autores principales:	Rajendra Upadhya, Lorina G. Baker, Woei C. Lam, Charles A. Specht, Maureen J. Donlin, Jennifer K. Lodge
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	chitin deacetylase catalytic site cell wall localization chitosan metal binding site fungal virulence Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d6e613ec492c4b0b8e3f5e22fe269e90
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spelling	oai:doaj.org-article:d6e613ec492c4b0b8e3f5e22fe269e902021-11-15T15:52:19Z<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Cda1 and Its Chitin Deacetylase Activity Are Required for Fungal Pathogenesis10.1128/mBio.02087-182150-7511https://doaj.org/article/d6e613ec492c4b0b8e3f5e22fe269e902018-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02087-18https://doaj.org/toc/2150-7511ABSTRACT Chitin is an essential component of the cell wall of Cryptococcus neoformans conferring structural rigidity and integrity under diverse environmental conditions. Chitin deacetylase genes encode the enyzmes (chitin deacetylases [Cdas]) that deacetylate chitin, converting it to chitosan. The functional role of chitosan in the fungal cell wall is not well defined, but it is an important virulence determinant of C. neoformans. Mutant strains deficient in chitosan are completely avirulent in a mouse pulmonary infection model. C. neoformans carries genes that encode three Cdas (Cda1, Cda2, and Cda3) that appear to be functionally redundant in cells grown under vegetative conditions. Here we report that C. neoformans Cda1 is the principal Cda responsible for fungal pathogenesis. Point mutations were introduced in the active site of Cda1 to generate strains in which the enzyme activity of Cda1 was abolished without perturbing either its stability or localization. When used to infect CBA/J mice, Cda1 mutant strains produced less chitosan and were attenuated for virulence. We further demonstrate that C. neoformans Cda genes are transcribed differently during a murine infection from what has been measured in vitro. IMPORTANCE Cryptococcus neoformans is unique among fungal pathogens that cause disease in a mammalian host, as it secretes a polysaccharide capsule that hinders recognition by the host to facilitate its survival and proliferation. Even though it causes serious infections in immunocompromised hosts, reports of infection in hosts that are immunocompetent are on the rise. The cell wall of a fungal pathogen, its synthesis, composition, and pathways of remodelling are attractive therapeutic targets for the development of fungicides. Chitosan, a polysaccharide in the cell wall of C. neoformans is one such target, as it is critical for pathogenesis and absent in the host. The results we present shed light on the importance of one of the chitin deacetylases that synthesize chitosan during infection and further implicates chitosan as being a critical factor for the pathogenesis of C. neoformans.Rajendra UpadhyaLorina G. BakerWoei C. LamCharles A. SpechtMaureen J. DonlinJennifer K. LodgeAmerican Society for Microbiologyarticlechitin deacetylasecatalytic sitecell wall localizationchitosanmetal binding sitefungal virulenceMicrobiologyQR1-502ENmBio, Vol 9, Iss 6 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	chitin deacetylase catalytic site cell wall localization chitosan metal binding site fungal virulence Microbiology QR1-502
spellingShingle	chitin deacetylase catalytic site cell wall localization chitosan metal binding site fungal virulence Microbiology QR1-502 Rajendra Upadhya Lorina G. Baker Woei C. Lam Charles A. Specht Maureen J. Donlin Jennifer K. Lodge <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Cda1 and Its Chitin Deacetylase Activity Are Required for Fungal Pathogenesis
description	ABSTRACT Chitin is an essential component of the cell wall of Cryptococcus neoformans conferring structural rigidity and integrity under diverse environmental conditions. Chitin deacetylase genes encode the enyzmes (chitin deacetylases [Cdas]) that deacetylate chitin, converting it to chitosan. The functional role of chitosan in the fungal cell wall is not well defined, but it is an important virulence determinant of C. neoformans. Mutant strains deficient in chitosan are completely avirulent in a mouse pulmonary infection model. C. neoformans carries genes that encode three Cdas (Cda1, Cda2, and Cda3) that appear to be functionally redundant in cells grown under vegetative conditions. Here we report that C. neoformans Cda1 is the principal Cda responsible for fungal pathogenesis. Point mutations were introduced in the active site of Cda1 to generate strains in which the enzyme activity of Cda1 was abolished without perturbing either its stability or localization. When used to infect CBA/J mice, Cda1 mutant strains produced less chitosan and were attenuated for virulence. We further demonstrate that C. neoformans Cda genes are transcribed differently during a murine infection from what has been measured in vitro. IMPORTANCE Cryptococcus neoformans is unique among fungal pathogens that cause disease in a mammalian host, as it secretes a polysaccharide capsule that hinders recognition by the host to facilitate its survival and proliferation. Even though it causes serious infections in immunocompromised hosts, reports of infection in hosts that are immunocompetent are on the rise. The cell wall of a fungal pathogen, its synthesis, composition, and pathways of remodelling are attractive therapeutic targets for the development of fungicides. Chitosan, a polysaccharide in the cell wall of C. neoformans is one such target, as it is critical for pathogenesis and absent in the host. The results we present shed light on the importance of one of the chitin deacetylases that synthesize chitosan during infection and further implicates chitosan as being a critical factor for the pathogenesis of C. neoformans.
format	article
author	Rajendra Upadhya Lorina G. Baker Woei C. Lam Charles A. Specht Maureen J. Donlin Jennifer K. Lodge
author_facet	Rajendra Upadhya Lorina G. Baker Woei C. Lam Charles A. Specht Maureen J. Donlin Jennifer K. Lodge
author_sort	Rajendra Upadhya
title	<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Cda1 and Its Chitin Deacetylase Activity Are Required for Fungal Pathogenesis
title_short	<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Cda1 and Its Chitin Deacetylase Activity Are Required for Fungal Pathogenesis
title_full	<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Cda1 and Its Chitin Deacetylase Activity Are Required for Fungal Pathogenesis
title_fullStr	<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Cda1 and Its Chitin Deacetylase Activity Are Required for Fungal Pathogenesis
title_full_unstemmed	<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Cda1 and Its Chitin Deacetylase Activity Are Required for Fungal Pathogenesis
title_sort	<named-content content-type="genus-species">cryptococcus neoformans</named-content> cda1 and its chitin deacetylase activity are required for fungal pathogenesis
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/d6e613ec492c4b0b8e3f5e22fe269e90
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<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Cda1 and Its Chitin Deacetylase Activity Are Required for Fungal Pathogenesis

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