A Genome-Wide Screen of Deletion Mutants in the Filamentous <named-content content-type="genus-species">Saccharomyces cerevisiae</named-content> Background Identifies Ergosterol as a Direct Trigger of Macrophage Pyroptosis

ABSTRACT Phagocytic cells such as macrophages play an important role in the host defense mechanisms mounted in response to the common human fungal pathogen Candida albicans. In vitro, C. albicans triggers macrophage NLRP3-Casp1/11-mediated pyroptosis, an inflammatory programmed cell death pathway. H...

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Autores principales:	Kristy Koselny, Nebibe Mutlu, Annabel Y. Minard, Anuj Kumar, Damian J. Krysan, Melanie Wellington
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Candida albicans inflammasome pyroptosis Microbiology QR1-502
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spelling	oai:doaj.org-article:5a846ae95af84dc7bb223534374728312021-11-15T16:00:14ZA Genome-Wide Screen of Deletion Mutants in the Filamentous <named-content content-type="genus-species">Saccharomyces cerevisiae</named-content> Background Identifies Ergosterol as a Direct Trigger of Macrophage Pyroptosis10.1128/mBio.01204-182150-7511https://doaj.org/article/5a846ae95af84dc7bb223534374728312018-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01204-18https://doaj.org/toc/2150-7511ABSTRACT Phagocytic cells such as macrophages play an important role in the host defense mechanisms mounted in response to the common human fungal pathogen Candida albicans. In vitro, C. albicans triggers macrophage NLRP3-Casp1/11-mediated pyroptosis, an inflammatory programmed cell death pathway. Here, we provide evidence that Casp1/11-dependent pyroptosis occurs in the kidney of infected mice during the early stages of infection. We have also used a genome-wide screen of nonessential Σ1278b Saccharomyces cerevisiae genes to identify genes required for yeast-triggered macrophage pyroptosis. The set of genes identified by this screen was enriched for those with functions in lipid and sterol homeostasis and trafficking. These observations led us to discover that cell surface localization and/or total levels of ergosterol correlate with the ability of S. cerevisiae, C. albicans, and Cryptococcus neoformans to trigger pyroptosis. Since the mammalian sterol cholesterol triggers NLRP3-mediated pyroptosis, we hypothesized that ergosterol may also do so. Consistent with that hypothesis, ergosterol-containing liposomes but not ergosterol-free liposomes induce pyroptosis. Cell wall mannoproteins directly bind ergosterol, and we found that Dan1, an ergosterol receptor mannoprotein, as well as specific mannosyltransferases, is required for pyroptosis, suggesting that cell wall-associated ergosterol may mediate the process. Taken together, these data indicate that ergosterol, like mammalian cholesterol, plays a direct role in yeast-mediated pyroptosis. IMPORTANCE Innate immune cells such as macrophages are key components of the host response to the human fungal pathogen Candida albicans. Macrophages undergo pyroptosis, an inflammatory, programmed cell death, in response to some species of pathogenic yeast. Prior to the work described in this report, yeast-triggered pyroptosis has been observed only in vitro; here, we show that pyroptosis occurs in the initial stages of murine kidney infection, suggesting that it plays an important role in the initial response of the innate immune system to invasive yeast infection. We also show that a key component of the fungal plasma membrane, ergosterol, directly triggers pyroptosis. Ergosterol is also present in the fungal cell wall, most likely associated with mannoproteins, and is increased in hyphal cells compared to yeast cells. Our data indicate that specific mannoproteins are required for pyroptosis. This is consistent with a potential mechanism whereby ergosterol present in the outer mannoprotein layer of the cell wall is accessible to the macrophage-mediated process. Taken together, our data provide the first evidence that ergosterol plays a direct role in the host-pathogen interactions of fungi.Kristy KoselnyNebibe MutluAnnabel Y. MinardAnuj KumarDamian J. KrysanMelanie WellingtonAmerican Society for MicrobiologyarticleCandida albicansinflammasomepyroptosisMicrobiologyQR1-502ENmBio, Vol 9, Iss 4 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Candida albicans inflammasome pyroptosis Microbiology QR1-502
spellingShingle	Candida albicans inflammasome pyroptosis Microbiology QR1-502 Kristy Koselny Nebibe Mutlu Annabel Y. Minard Anuj Kumar Damian J. Krysan Melanie Wellington A Genome-Wide Screen of Deletion Mutants in the Filamentous <named-content content-type="genus-species">Saccharomyces cerevisiae</named-content> Background Identifies Ergosterol as a Direct Trigger of Macrophage Pyroptosis
description	ABSTRACT Phagocytic cells such as macrophages play an important role in the host defense mechanisms mounted in response to the common human fungal pathogen Candida albicans. In vitro, C. albicans triggers macrophage NLRP3-Casp1/11-mediated pyroptosis, an inflammatory programmed cell death pathway. Here, we provide evidence that Casp1/11-dependent pyroptosis occurs in the kidney of infected mice during the early stages of infection. We have also used a genome-wide screen of nonessential Σ1278b Saccharomyces cerevisiae genes to identify genes required for yeast-triggered macrophage pyroptosis. The set of genes identified by this screen was enriched for those with functions in lipid and sterol homeostasis and trafficking. These observations led us to discover that cell surface localization and/or total levels of ergosterol correlate with the ability of S. cerevisiae, C. albicans, and Cryptococcus neoformans to trigger pyroptosis. Since the mammalian sterol cholesterol triggers NLRP3-mediated pyroptosis, we hypothesized that ergosterol may also do so. Consistent with that hypothesis, ergosterol-containing liposomes but not ergosterol-free liposomes induce pyroptosis. Cell wall mannoproteins directly bind ergosterol, and we found that Dan1, an ergosterol receptor mannoprotein, as well as specific mannosyltransferases, is required for pyroptosis, suggesting that cell wall-associated ergosterol may mediate the process. Taken together, these data indicate that ergosterol, like mammalian cholesterol, plays a direct role in yeast-mediated pyroptosis. IMPORTANCE Innate immune cells such as macrophages are key components of the host response to the human fungal pathogen Candida albicans. Macrophages undergo pyroptosis, an inflammatory, programmed cell death, in response to some species of pathogenic yeast. Prior to the work described in this report, yeast-triggered pyroptosis has been observed only in vitro; here, we show that pyroptosis occurs in the initial stages of murine kidney infection, suggesting that it plays an important role in the initial response of the innate immune system to invasive yeast infection. We also show that a key component of the fungal plasma membrane, ergosterol, directly triggers pyroptosis. Ergosterol is also present in the fungal cell wall, most likely associated with mannoproteins, and is increased in hyphal cells compared to yeast cells. Our data indicate that specific mannoproteins are required for pyroptosis. This is consistent with a potential mechanism whereby ergosterol present in the outer mannoprotein layer of the cell wall is accessible to the macrophage-mediated process. Taken together, our data provide the first evidence that ergosterol plays a direct role in the host-pathogen interactions of fungi.
format	article
author	Kristy Koselny Nebibe Mutlu Annabel Y. Minard Anuj Kumar Damian J. Krysan Melanie Wellington
author_facet	Kristy Koselny Nebibe Mutlu Annabel Y. Minard Anuj Kumar Damian J. Krysan Melanie Wellington
author_sort	Kristy Koselny
title	A Genome-Wide Screen of Deletion Mutants in the Filamentous <named-content content-type="genus-species">Saccharomyces cerevisiae</named-content> Background Identifies Ergosterol as a Direct Trigger of Macrophage Pyroptosis
title_short	A Genome-Wide Screen of Deletion Mutants in the Filamentous <named-content content-type="genus-species">Saccharomyces cerevisiae</named-content> Background Identifies Ergosterol as a Direct Trigger of Macrophage Pyroptosis
title_full	A Genome-Wide Screen of Deletion Mutants in the Filamentous <named-content content-type="genus-species">Saccharomyces cerevisiae</named-content> Background Identifies Ergosterol as a Direct Trigger of Macrophage Pyroptosis
title_fullStr	A Genome-Wide Screen of Deletion Mutants in the Filamentous <named-content content-type="genus-species">Saccharomyces cerevisiae</named-content> Background Identifies Ergosterol as a Direct Trigger of Macrophage Pyroptosis
title_full_unstemmed	A Genome-Wide Screen of Deletion Mutants in the Filamentous <named-content content-type="genus-species">Saccharomyces cerevisiae</named-content> Background Identifies Ergosterol as a Direct Trigger of Macrophage Pyroptosis
title_sort	genome-wide screen of deletion mutants in the filamentous <named-content content-type="genus-species">saccharomyces cerevisiae</named-content> background identifies ergosterol as a direct trigger of macrophage pyroptosis
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/5a846ae95af84dc7bb22353437472831
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A Genome-Wide Screen of Deletion Mutants in the Filamentous <named-content content-type="genus-species">Saccharomyces cerevisiae</named-content> Background Identifies Ergosterol as a Direct Trigger of Macrophage Pyroptosis

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