Phagosomal F-Actin Retention by <named-content content-type="genus-species">Cryptococcus gattii</named-content> Induces Dendritic Cell Immunoparalysis

ABSTRACT Cryptococcus gattii is a major cause of life-threatening mycosis in immunocompetent individuals and responsible for the ongoing epidemic outbreak of cryptococcosis in the Pacific Northwest of North America. This deadly fungus is known to evade important host immune responses, including dend...

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Autores principales:	Khusraw Jamil, Maria J. Polyak, David D. Feehan, Philip Surmanowicz, Danuta Stack, Shu Shun Li, Henry Ogbomo, Michal Olszewski, Anutosh Ganguly, Christopher H. Mody
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Cryptococcus gattii dendritic cells immune evasion immunoparalysis phagosomal F-actin Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/92baed861cf74c3389130aba7d91830a
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spelling	oai:doaj.org-article:92baed861cf74c3389130aba7d91830a2021-11-15T15:55:43ZPhagosomal F-Actin Retention by <named-content content-type="genus-species">Cryptococcus gattii</named-content> Induces Dendritic Cell Immunoparalysis10.1128/mBio.01821-202150-7511https://doaj.org/article/92baed861cf74c3389130aba7d91830a2020-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01821-20https://doaj.org/toc/2150-7511ABSTRACT Cryptococcus gattii is a major cause of life-threatening mycosis in immunocompetent individuals and responsible for the ongoing epidemic outbreak of cryptococcosis in the Pacific Northwest of North America. This deadly fungus is known to evade important host immune responses, including dendritic cell (DC) maturation and concomitant T cell immunity, via immune evasion mechanisms that remain unclear. Here, we demonstrate that primary human DCs phagocytose C. gattii but the maturation of phagosomes to phagolysosomes was blocked as a result of sustained filamentous actin (F-actin) that entrapped and concealed the phagosomes from recognition. Superresolution structured illumination microscopy (SR-SIM) revealed that the persistent phagosomal F-actin formed a cage-like structure that sterically hindered and functionally blocked the fusion of lysosomes. Blocking lysosome fusion was sufficient to inhibit phagosomal acidification and subsequent intracellular fungal killing by DCs. Retention of phagosomal F-actin by C. gattii also caused DC immunoparalysis. Disrupting the retained F-actin cage with cytochalasin D not only restored DC phagosomal maturation but also promoted DC costimulatory maturation and robust T cell activation and proliferation. Collectively, these results reveal a unique mechanism of DC immune evasion that enhances intracellular fungal pathogenicity and may explain suppressed cell-mediated immunity. IMPORTANCE Cryptococcus yeast species typically display characteristics of opportunistic pathogens, with the exception of C. gattii, which can cause life-threatening respiratory and disseminated brain infections in otherwise healthy people. The pathogenesis of C. gattii is not well understood, but an important characteristic is that C. gattii is capable of evading host cell-mediated immune defenses initiated by DCs. Here, we report that when virulent C. gattii becomes ingested by a DC, the intracellular compartment containing the fungi is covered by a persistent protein cage structure consisting of F-actin. This F-actin cage acts as a barrier to prevent interaction with other intracellular compartments, and as a result, the DC fails to kill the fungi and activate important cell-mediated immune responses. We propose that this unique immune evasion mechanism permits C. gattii to remain unchallenged within host cells, leading to persistent infection.Khusraw JamilMaria J. PolyakDavid D. FeehanPhilip SurmanowiczDanuta StackShu Shun LiHenry OgbomoMichal OlszewskiAnutosh GangulyChristopher H. ModyAmerican Society for MicrobiologyarticleCryptococcus gattiidendritic cellsimmune evasionimmunoparalysisphagosomal F-actinMicrobiologyQR1-502ENmBio, Vol 11, Iss 6 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cryptococcus gattii dendritic cells immune evasion immunoparalysis phagosomal F-actin Microbiology QR1-502
spellingShingle	Cryptococcus gattii dendritic cells immune evasion immunoparalysis phagosomal F-actin Microbiology QR1-502 Khusraw Jamil Maria J. Polyak David D. Feehan Philip Surmanowicz Danuta Stack Shu Shun Li Henry Ogbomo Michal Olszewski Anutosh Ganguly Christopher H. Mody Phagosomal F-Actin Retention by <named-content content-type="genus-species">Cryptococcus gattii</named-content> Induces Dendritic Cell Immunoparalysis
description	ABSTRACT Cryptococcus gattii is a major cause of life-threatening mycosis in immunocompetent individuals and responsible for the ongoing epidemic outbreak of cryptococcosis in the Pacific Northwest of North America. This deadly fungus is known to evade important host immune responses, including dendritic cell (DC) maturation and concomitant T cell immunity, via immune evasion mechanisms that remain unclear. Here, we demonstrate that primary human DCs phagocytose C. gattii but the maturation of phagosomes to phagolysosomes was blocked as a result of sustained filamentous actin (F-actin) that entrapped and concealed the phagosomes from recognition. Superresolution structured illumination microscopy (SR-SIM) revealed that the persistent phagosomal F-actin formed a cage-like structure that sterically hindered and functionally blocked the fusion of lysosomes. Blocking lysosome fusion was sufficient to inhibit phagosomal acidification and subsequent intracellular fungal killing by DCs. Retention of phagosomal F-actin by C. gattii also caused DC immunoparalysis. Disrupting the retained F-actin cage with cytochalasin D not only restored DC phagosomal maturation but also promoted DC costimulatory maturation and robust T cell activation and proliferation. Collectively, these results reveal a unique mechanism of DC immune evasion that enhances intracellular fungal pathogenicity and may explain suppressed cell-mediated immunity. IMPORTANCE Cryptococcus yeast species typically display characteristics of opportunistic pathogens, with the exception of C. gattii, which can cause life-threatening respiratory and disseminated brain infections in otherwise healthy people. The pathogenesis of C. gattii is not well understood, but an important characteristic is that C. gattii is capable of evading host cell-mediated immune defenses initiated by DCs. Here, we report that when virulent C. gattii becomes ingested by a DC, the intracellular compartment containing the fungi is covered by a persistent protein cage structure consisting of F-actin. This F-actin cage acts as a barrier to prevent interaction with other intracellular compartments, and as a result, the DC fails to kill the fungi and activate important cell-mediated immune responses. We propose that this unique immune evasion mechanism permits C. gattii to remain unchallenged within host cells, leading to persistent infection.
format	article
author	Khusraw Jamil Maria J. Polyak David D. Feehan Philip Surmanowicz Danuta Stack Shu Shun Li Henry Ogbomo Michal Olszewski Anutosh Ganguly Christopher H. Mody
author_facet	Khusraw Jamil Maria J. Polyak David D. Feehan Philip Surmanowicz Danuta Stack Shu Shun Li Henry Ogbomo Michal Olszewski Anutosh Ganguly Christopher H. Mody
author_sort	Khusraw Jamil
title	Phagosomal F-Actin Retention by <named-content content-type="genus-species">Cryptococcus gattii</named-content> Induces Dendritic Cell Immunoparalysis
title_short	Phagosomal F-Actin Retention by <named-content content-type="genus-species">Cryptococcus gattii</named-content> Induces Dendritic Cell Immunoparalysis
title_full	Phagosomal F-Actin Retention by <named-content content-type="genus-species">Cryptococcus gattii</named-content> Induces Dendritic Cell Immunoparalysis
title_fullStr	Phagosomal F-Actin Retention by <named-content content-type="genus-species">Cryptococcus gattii</named-content> Induces Dendritic Cell Immunoparalysis
title_full_unstemmed	Phagosomal F-Actin Retention by <named-content content-type="genus-species">Cryptococcus gattii</named-content> Induces Dendritic Cell Immunoparalysis
title_sort	phagosomal f-actin retention by <named-content content-type="genus-species">cryptococcus gattii</named-content> induces dendritic cell immunoparalysis
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/92baed861cf74c3389130aba7d91830a
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Phagosomal F-Actin Retention by <named-content content-type="genus-species">Cryptococcus gattii</named-content> Induces Dendritic Cell Immunoparalysis

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