High-Throughput Screening Identifies Genes Required for <italic toggle="yes">Candida albicans</italic> Induction of Macrophage Pyroptosis

ABSTRACT The innate immune system is the first line of defense against invasive fungal infections. As a consequence, many successful fungal pathogens have evolved elegant strategies to interact with host immune cells. For example, Candida albicans undergoes a morphogenetic switch coupled to cell wal...

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Autores principales:	Teresa R. O’Meara, Kwamaa Duah, Cynthia X. Guo, Michelle E. Maxson, Ryan G. Gaudet, Kristy Koselny, Melanie Wellington, Michael E. Powers, Jessie MacAlpine, Matthew J. O’Meara, Amanda O. Veri, Sergio Grinstein, Suzanne M. Noble, Damian Krysan, Scott D. Gray-Owen, Leah E. Cowen
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Candida cell wall remodelling functional genomics fungal morphogenesis fungal pathogenesis host-pathogen interaction Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/37c1c8c11e4b4ed3843ff6f59b92ef9d
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spelling	oai:doaj.org-article:37c1c8c11e4b4ed3843ff6f59b92ef9d2021-11-15T16:00:15ZHigh-Throughput Screening Identifies Genes Required for <italic toggle="yes">Candida albicans</italic> Induction of Macrophage Pyroptosis10.1128/mBio.01581-182150-7511https://doaj.org/article/37c1c8c11e4b4ed3843ff6f59b92ef9d2018-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01581-18https://doaj.org/toc/2150-7511ABSTRACT The innate immune system is the first line of defense against invasive fungal infections. As a consequence, many successful fungal pathogens have evolved elegant strategies to interact with host immune cells. For example, Candida albicans undergoes a morphogenetic switch coupled to cell wall remodeling upon phagocytosis by macrophages and then induces macrophage pyroptosis, an inflammatory cell death program. To elucidate the genetic circuitry through which C. albicans orchestrates this host response, we performed the first large-scale analysis of C. albicans interactions with mammalian immune cells. We identified 98 C. albicans genes that enable macrophage pyroptosis without influencing fungal cell morphology in the macrophage, including specific determinants of cell wall biogenesis and the Hog1 signaling cascade. Using these mutated genes, we discovered that defects in the activation of pyroptosis affect immune cell recruitment during infection. Examining host circuitry required for pyroptosis in response to C. albicans infection, we discovered that inflammasome priming and activation can be decoupled. Finally, we observed that apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization can occur prior to phagolysosomal rupture by C. albicans hyphae, demonstrating that phagolysosomal rupture is not the inflammasome activating signal. Taking the data together, this work defines genes that enable fungal cell wall remodeling and activation of macrophage pyroptosis independently of effects on morphogenesis and identifies macrophage signaling components that are required for pyroptosis in response to C. albicans infection. IMPORTANCE Candida albicans is a natural member of the human mucosal microbiota that can also cause superficial infections and life-threatening systemic infections, both of which are characterized by inflammation. Host defense relies mainly on the ingestion and destruction of C. albicans by innate immune cells, such as macrophages and neutrophils. Although some C. albicans cells are killed by macrophages, most undergo a morphological change and escape by inducing macrophage pyroptosis. Here, we investigated the C. albicans genes and host factors that promote macrophage pyroptosis in response to intracellular fungi. This work provides a foundation for understanding how host immune cells interact with C. albicans and may lead to effective strategies to modulate inflammation induced by fungal infections.Teresa R. O’MearaKwamaa DuahCynthia X. GuoMichelle E. MaxsonRyan G. GaudetKristy KoselnyMelanie WellingtonMichael E. PowersJessie MacAlpineMatthew J. O’MearaAmanda O. VeriSergio GrinsteinSuzanne M. NobleDamian KrysanScott D. Gray-OwenLeah E. CowenAmerican Society for MicrobiologyarticleCandidacell wall remodellingfunctional genomicsfungal morphogenesisfungal pathogenesishost-pathogen interactionMicrobiologyQR1-502ENmBio, Vol 9, Iss 4 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Candida cell wall remodelling functional genomics fungal morphogenesis fungal pathogenesis host-pathogen interaction Microbiology QR1-502
spellingShingle	Candida cell wall remodelling functional genomics fungal morphogenesis fungal pathogenesis host-pathogen interaction Microbiology QR1-502 Teresa R. O’Meara Kwamaa Duah Cynthia X. Guo Michelle E. Maxson Ryan G. Gaudet Kristy Koselny Melanie Wellington Michael E. Powers Jessie MacAlpine Matthew J. O’Meara Amanda O. Veri Sergio Grinstein Suzanne M. Noble Damian Krysan Scott D. Gray-Owen Leah E. Cowen High-Throughput Screening Identifies Genes Required for <italic toggle="yes">Candida albicans</italic> Induction of Macrophage Pyroptosis
description	ABSTRACT The innate immune system is the first line of defense against invasive fungal infections. As a consequence, many successful fungal pathogens have evolved elegant strategies to interact with host immune cells. For example, Candida albicans undergoes a morphogenetic switch coupled to cell wall remodeling upon phagocytosis by macrophages and then induces macrophage pyroptosis, an inflammatory cell death program. To elucidate the genetic circuitry through which C. albicans orchestrates this host response, we performed the first large-scale analysis of C. albicans interactions with mammalian immune cells. We identified 98 C. albicans genes that enable macrophage pyroptosis without influencing fungal cell morphology in the macrophage, including specific determinants of cell wall biogenesis and the Hog1 signaling cascade. Using these mutated genes, we discovered that defects in the activation of pyroptosis affect immune cell recruitment during infection. Examining host circuitry required for pyroptosis in response to C. albicans infection, we discovered that inflammasome priming and activation can be decoupled. Finally, we observed that apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization can occur prior to phagolysosomal rupture by C. albicans hyphae, demonstrating that phagolysosomal rupture is not the inflammasome activating signal. Taking the data together, this work defines genes that enable fungal cell wall remodeling and activation of macrophage pyroptosis independently of effects on morphogenesis and identifies macrophage signaling components that are required for pyroptosis in response to C. albicans infection. IMPORTANCE Candida albicans is a natural member of the human mucosal microbiota that can also cause superficial infections and life-threatening systemic infections, both of which are characterized by inflammation. Host defense relies mainly on the ingestion and destruction of C. albicans by innate immune cells, such as macrophages and neutrophils. Although some C. albicans cells are killed by macrophages, most undergo a morphological change and escape by inducing macrophage pyroptosis. Here, we investigated the C. albicans genes and host factors that promote macrophage pyroptosis in response to intracellular fungi. This work provides a foundation for understanding how host immune cells interact with C. albicans and may lead to effective strategies to modulate inflammation induced by fungal infections.
format	article
author	Teresa R. O’Meara Kwamaa Duah Cynthia X. Guo Michelle E. Maxson Ryan G. Gaudet Kristy Koselny Melanie Wellington Michael E. Powers Jessie MacAlpine Matthew J. O’Meara Amanda O. Veri Sergio Grinstein Suzanne M. Noble Damian Krysan Scott D. Gray-Owen Leah E. Cowen
author_facet	Teresa R. O’Meara Kwamaa Duah Cynthia X. Guo Michelle E. Maxson Ryan G. Gaudet Kristy Koselny Melanie Wellington Michael E. Powers Jessie MacAlpine Matthew J. O’Meara Amanda O. Veri Sergio Grinstein Suzanne M. Noble Damian Krysan Scott D. Gray-Owen Leah E. Cowen
author_sort	Teresa R. O’Meara
title	High-Throughput Screening Identifies Genes Required for <italic toggle="yes">Candida albicans</italic> Induction of Macrophage Pyroptosis
title_short	High-Throughput Screening Identifies Genes Required for <italic toggle="yes">Candida albicans</italic> Induction of Macrophage Pyroptosis
title_full	High-Throughput Screening Identifies Genes Required for <italic toggle="yes">Candida albicans</italic> Induction of Macrophage Pyroptosis
title_fullStr	High-Throughput Screening Identifies Genes Required for <italic toggle="yes">Candida albicans</italic> Induction of Macrophage Pyroptosis
title_full_unstemmed	High-Throughput Screening Identifies Genes Required for <italic toggle="yes">Candida albicans</italic> Induction of Macrophage Pyroptosis
title_sort	high-throughput screening identifies genes required for <italic toggle="yes">candida albicans</italic> induction of macrophage pyroptosis
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/37c1c8c11e4b4ed3843ff6f59b92ef9d
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High-Throughput Screening Identifies Genes Required for <italic toggle="yes">Candida albicans</italic> Induction of Macrophage Pyroptosis

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