The Endoplasmic Reticulum-Mitochondrion Tether ERMES Orchestrates Fungal Immune Evasion, Illuminating Inflammasome Responses to Hyphal Signals

ABSTRACT The pathogenic yeast Candida albicans escapes macrophages by triggering NLRP3 inflammasome-dependent host cell death (pyroptosis). Pyroptosis is inflammatory and must be tightly regulated by host and microbe, but the mechanism is incompletely defined. We characterized the C. albicans endopl...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Timothy M. Tucey, Jiyoti Verma-Gaur, Julie Nguyen, Victoria L. Hewitt, Tricia L. Lo, Miguel Shingu-Vazquez, Avril A. B. Robertson, James R. Hill, Filomena A. Pettolino, Travis Beddoe, Matthew A. Cooper, Thomas Naderer, Ana Traven
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Candida albicans macrophage metabolism mitochondria Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9250ecd36c7f4b649bfd1f5e5382377f
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:9250ecd36c7f4b649bfd1f5e5382377f
record_format	dspace
spelling	oai:doaj.org-article:9250ecd36c7f4b649bfd1f5e5382377f2021-11-15T15:21:18ZThe Endoplasmic Reticulum-Mitochondrion Tether ERMES Orchestrates Fungal Immune Evasion, Illuminating Inflammasome Responses to Hyphal Signals10.1128/mSphere.00074-162379-5042https://doaj.org/article/9250ecd36c7f4b649bfd1f5e5382377f2016-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00074-16https://doaj.org/toc/2379-5042ABSTRACT The pathogenic yeast Candida albicans escapes macrophages by triggering NLRP3 inflammasome-dependent host cell death (pyroptosis). Pyroptosis is inflammatory and must be tightly regulated by host and microbe, but the mechanism is incompletely defined. We characterized the C. albicans endoplasmic reticulum (ER)-mitochondrion tether ERMES and show that the ERMES mmm1 mutant is severely crippled in killing macrophages despite hyphal formation and normal phagocytosis and survival. To understand dynamic inflammasome responses to Candida with high spatiotemporal resolution, we established live-cell imaging for parallel detection of inflammasome activation and pyroptosis at the single-cell level. This showed that the inflammasome response to mmm1 mutant hyphae is delayed by 10 h, after which an exacerbated activation occurs. The NLRP3 inhibitor MCC950 inhibited inflammasome activation and pyroptosis by C. albicans, including exacerbated inflammasome activation by the mmm1 mutant. At the cell biology level, inactivation of ERMES led to a rapid collapse of mitochondrial tubular morphology, slow growth and hyphal elongation at host temperature, and reduced exposed 1,3-β-glucan in hyphal populations. Our data suggest that inflammasome activation by C. albicans requires a signal threshold dependent on hyphal elongation and cell wall remodeling, which could fine-tune the response relative to the level of danger posed by C. albicans. The phenotypes of the ERMES mutant and the lack of conservation in animals suggest that ERMES is a promising antifungal drug target. Our data further indicate that NLRP3 inhibition by MCC950 could modulate C. albicans-induced inflammation. IMPORTANCE The yeast Candida albicans causes human infections that have mortality rates approaching 50%. The key to developing improved therapeutics is to understand the host-pathogen interface. A critical interaction is that with macrophages: intracellular Candida triggers the NLRP3/caspase-1 inflammasome for escape through lytic host cell death, but this also activates antifungal responses. To better understand how the inflammasome response to Candida is fine-tuned, we established live-cell imaging of inflammasome activation at single-cell resolution, coupled with analysis of the fungal ERMES complex, a mitochondrial regulator that lacks human homologs. We show that ERMES mediates Candida escape via inflammasome-dependent processes, and our data suggest that inflammasome activation is controlled by the level of hyphal growth and exposure of cell wall components as a proxy for severity of danger. Our study provides the most detailed dynamic analysis of inflammasome responses to a fungal pathogen so far and establishes promising pathogen- and host-derived therapeutic strategies.Timothy M. TuceyJiyoti Verma-GaurJulie NguyenVictoria L. HewittTricia L. LoMiguel Shingu-VazquezAvril A. B. RobertsonJames R. HillFilomena A. PettolinoTravis BeddoeMatthew A. CooperThomas NadererAna TravenAmerican Society for MicrobiologyarticleCandida albicansmacrophagemetabolismmitochondriaMicrobiologyQR1-502ENmSphere, Vol 1, Iss 3 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Candida albicans macrophage metabolism mitochondria Microbiology QR1-502
spellingShingle	Candida albicans macrophage metabolism mitochondria Microbiology QR1-502 Timothy M. Tucey Jiyoti Verma-Gaur Julie Nguyen Victoria L. Hewitt Tricia L. Lo Miguel Shingu-Vazquez Avril A. B. Robertson James R. Hill Filomena A. Pettolino Travis Beddoe Matthew A. Cooper Thomas Naderer Ana Traven The Endoplasmic Reticulum-Mitochondrion Tether ERMES Orchestrates Fungal Immune Evasion, Illuminating Inflammasome Responses to Hyphal Signals
description	ABSTRACT The pathogenic yeast Candida albicans escapes macrophages by triggering NLRP3 inflammasome-dependent host cell death (pyroptosis). Pyroptosis is inflammatory and must be tightly regulated by host and microbe, but the mechanism is incompletely defined. We characterized the C. albicans endoplasmic reticulum (ER)-mitochondrion tether ERMES and show that the ERMES mmm1 mutant is severely crippled in killing macrophages despite hyphal formation and normal phagocytosis and survival. To understand dynamic inflammasome responses to Candida with high spatiotemporal resolution, we established live-cell imaging for parallel detection of inflammasome activation and pyroptosis at the single-cell level. This showed that the inflammasome response to mmm1 mutant hyphae is delayed by 10 h, after which an exacerbated activation occurs. The NLRP3 inhibitor MCC950 inhibited inflammasome activation and pyroptosis by C. albicans, including exacerbated inflammasome activation by the mmm1 mutant. At the cell biology level, inactivation of ERMES led to a rapid collapse of mitochondrial tubular morphology, slow growth and hyphal elongation at host temperature, and reduced exposed 1,3-β-glucan in hyphal populations. Our data suggest that inflammasome activation by C. albicans requires a signal threshold dependent on hyphal elongation and cell wall remodeling, which could fine-tune the response relative to the level of danger posed by C. albicans. The phenotypes of the ERMES mutant and the lack of conservation in animals suggest that ERMES is a promising antifungal drug target. Our data further indicate that NLRP3 inhibition by MCC950 could modulate C. albicans-induced inflammation. IMPORTANCE The yeast Candida albicans causes human infections that have mortality rates approaching 50%. The key to developing improved therapeutics is to understand the host-pathogen interface. A critical interaction is that with macrophages: intracellular Candida triggers the NLRP3/caspase-1 inflammasome for escape through lytic host cell death, but this also activates antifungal responses. To better understand how the inflammasome response to Candida is fine-tuned, we established live-cell imaging of inflammasome activation at single-cell resolution, coupled with analysis of the fungal ERMES complex, a mitochondrial regulator that lacks human homologs. We show that ERMES mediates Candida escape via inflammasome-dependent processes, and our data suggest that inflammasome activation is controlled by the level of hyphal growth and exposure of cell wall components as a proxy for severity of danger. Our study provides the most detailed dynamic analysis of inflammasome responses to a fungal pathogen so far and establishes promising pathogen- and host-derived therapeutic strategies.
format	article
author	Timothy M. Tucey Jiyoti Verma-Gaur Julie Nguyen Victoria L. Hewitt Tricia L. Lo Miguel Shingu-Vazquez Avril A. B. Robertson James R. Hill Filomena A. Pettolino Travis Beddoe Matthew A. Cooper Thomas Naderer Ana Traven
author_facet	Timothy M. Tucey Jiyoti Verma-Gaur Julie Nguyen Victoria L. Hewitt Tricia L. Lo Miguel Shingu-Vazquez Avril A. B. Robertson James R. Hill Filomena A. Pettolino Travis Beddoe Matthew A. Cooper Thomas Naderer Ana Traven
author_sort	Timothy M. Tucey
title	The Endoplasmic Reticulum-Mitochondrion Tether ERMES Orchestrates Fungal Immune Evasion, Illuminating Inflammasome Responses to Hyphal Signals
title_short	The Endoplasmic Reticulum-Mitochondrion Tether ERMES Orchestrates Fungal Immune Evasion, Illuminating Inflammasome Responses to Hyphal Signals
title_full	The Endoplasmic Reticulum-Mitochondrion Tether ERMES Orchestrates Fungal Immune Evasion, Illuminating Inflammasome Responses to Hyphal Signals
title_fullStr	The Endoplasmic Reticulum-Mitochondrion Tether ERMES Orchestrates Fungal Immune Evasion, Illuminating Inflammasome Responses to Hyphal Signals
title_full_unstemmed	The Endoplasmic Reticulum-Mitochondrion Tether ERMES Orchestrates Fungal Immune Evasion, Illuminating Inflammasome Responses to Hyphal Signals
title_sort	endoplasmic reticulum-mitochondrion tether ermes orchestrates fungal immune evasion, illuminating inflammasome responses to hyphal signals
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/9250ecd36c7f4b649bfd1f5e5382377f
work_keys_str_mv	AT timothymtucey theendoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT jiyotivermagaur theendoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT julienguyen theendoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT victorialhewitt theendoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT triciallo theendoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT miguelshinguvazquez theendoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT avrilabrobertson theendoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT jamesrhill theendoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT filomenaapettolino theendoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT travisbeddoe theendoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT matthewacooper theendoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT thomasnaderer theendoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT anatraven theendoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT timothymtucey endoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT jiyotivermagaur endoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT julienguyen endoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT victorialhewitt endoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT triciallo endoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT miguelshinguvazquez endoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT avrilabrobertson endoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT jamesrhill endoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT filomenaapettolino endoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT travisbeddoe endoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT matthewacooper endoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT thomasnaderer endoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals AT anatraven endoplasmicreticulummitochondriontetherermesorchestratesfungalimmuneevasionilluminatinginflammasomeresponsestohyphalsignals
_version_	1718428144665362432

The Endoplasmic Reticulum-Mitochondrion Tether ERMES Orchestrates Fungal Immune Evasion, Illuminating Inflammasome Responses to Hyphal Signals

Ejemplares similares