<italic toggle="yes">Yersinia pestis</italic> Targets the Host Endosome Recycling Pathway during the Biogenesis of the <italic toggle="yes">Yersinia</italic>-Containing Vacuole To Avoid Killing by Macrophages

ABSTRACT Yersinia pestis has evolved many strategies to evade the innate immune system. One of these strategies is the ability to survive within macrophages. Upon phagocytosis, Y. pestis prevents phagolysosome maturation and establishes a modified compartment termed the Yersinia-containing vacuole (...

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Autores principales:	Michael G. Connor, Amanda R. Pulsifer, Donghoon Chung, Eric C. Rouchka, Brian K. Ceresa, Matthew B. Lawrenz
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	intracellular survival plague Rab GTPases Yersinia pestis endosome recycling Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ebf5230a7fe84bf694570a581c136c84
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spelling	oai:doaj.org-article:ebf5230a7fe84bf694570a581c136c842021-11-15T15:53:25Z<italic toggle="yes">Yersinia pestis</italic> Targets the Host Endosome Recycling Pathway during the Biogenesis of the <italic toggle="yes">Yersinia</italic>-Containing Vacuole To Avoid Killing by Macrophages10.1128/mBio.01800-172150-7511https://doaj.org/article/ebf5230a7fe84bf694570a581c136c842018-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01800-17https://doaj.org/toc/2150-7511ABSTRACT Yersinia pestis has evolved many strategies to evade the innate immune system. One of these strategies is the ability to survive within macrophages. Upon phagocytosis, Y. pestis prevents phagolysosome maturation and establishes a modified compartment termed the Yersinia-containing vacuole (YCV). Y. pestis actively inhibits the acidification of this compartment, and eventually, the YCV transitions from a tight-fitting vacuole into a spacious replicative vacuole. The mechanisms to generate the YCV have not been defined. However, we hypothesized that YCV biogenesis requires Y. pestis interactions with specific host factors to subvert normal vesicular trafficking. In order to identify these factors, we performed a genome-wide RNA interference (RNAi) screen to identify host factors required for Y. pestis survival in macrophages. This screen revealed that 71 host proteins are required for intracellular survival of Y. pestis. Of particular interest was the enrichment for genes involved in endosome recycling. Moreover, we demonstrated that Y. pestis actively recruits Rab4a and Rab11b to the YCV in a type three secretion system-independent manner, indicating remodeling of the YCV by Y. pestis to resemble a recycling endosome. While recruitment of Rab4a was necessary to inhibit YCV acidification and lysosomal fusion early during infection, Rab11b appeared to contribute to later stages of YCV biogenesis. We also discovered that Y. pestis disrupts global host endocytic recycling in macrophages, possibly through sequestration of Rab11b, and this process is required for bacterial replication. These data provide the first evidence that Y. pestis targets the host endocytic recycling pathway to avoid phagolysosomal maturation and generate the YCV. IMPORTANCE Yersinia pestis can infect and survive within macrophages. However, the mechanisms that the bacterium use to subvert killing by these phagocytes have not been defined. To provide a better understanding of these mechanisms, we used an RNAi approach to identify host factors required for intracellular Y. pestis survival. This approach revealed that the host endocytic recycling pathway is essential for Y. pestis to avoid clearance by the macrophage. We further demonstrate that Y. pestis remodels the phagosome to resemble a recycling endosome, allowing the bacterium to avoid the normal phagolysosomal maturation pathway. Moreover, we show that infection with Y. pestis disrupts normal recycling in the macrophage and that disruption is required for bacterial replication. These findings provide the first evidence that Y. pestis targets the host endocytic recycling pathway in order to evade killing by macrophages.Michael G. ConnorAmanda R. PulsiferDonghoon ChungEric C. RouchkaBrian K. CeresaMatthew B. LawrenzAmerican Society for Microbiologyarticleintracellular survivalplagueRab GTPasesYersinia pestisendosome recyclingMicrobiologyQR1-502ENmBio, Vol 9, Iss 1 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	intracellular survival plague Rab GTPases Yersinia pestis endosome recycling Microbiology QR1-502
spellingShingle	intracellular survival plague Rab GTPases Yersinia pestis endosome recycling Microbiology QR1-502 Michael G. Connor Amanda R. Pulsifer Donghoon Chung Eric C. Rouchka Brian K. Ceresa Matthew B. Lawrenz <italic toggle="yes">Yersinia pestis</italic> Targets the Host Endosome Recycling Pathway during the Biogenesis of the <italic toggle="yes">Yersinia</italic>-Containing Vacuole To Avoid Killing by Macrophages
description	ABSTRACT Yersinia pestis has evolved many strategies to evade the innate immune system. One of these strategies is the ability to survive within macrophages. Upon phagocytosis, Y. pestis prevents phagolysosome maturation and establishes a modified compartment termed the Yersinia-containing vacuole (YCV). Y. pestis actively inhibits the acidification of this compartment, and eventually, the YCV transitions from a tight-fitting vacuole into a spacious replicative vacuole. The mechanisms to generate the YCV have not been defined. However, we hypothesized that YCV biogenesis requires Y. pestis interactions with specific host factors to subvert normal vesicular trafficking. In order to identify these factors, we performed a genome-wide RNA interference (RNAi) screen to identify host factors required for Y. pestis survival in macrophages. This screen revealed that 71 host proteins are required for intracellular survival of Y. pestis. Of particular interest was the enrichment for genes involved in endosome recycling. Moreover, we demonstrated that Y. pestis actively recruits Rab4a and Rab11b to the YCV in a type three secretion system-independent manner, indicating remodeling of the YCV by Y. pestis to resemble a recycling endosome. While recruitment of Rab4a was necessary to inhibit YCV acidification and lysosomal fusion early during infection, Rab11b appeared to contribute to later stages of YCV biogenesis. We also discovered that Y. pestis disrupts global host endocytic recycling in macrophages, possibly through sequestration of Rab11b, and this process is required for bacterial replication. These data provide the first evidence that Y. pestis targets the host endocytic recycling pathway to avoid phagolysosomal maturation and generate the YCV. IMPORTANCE Yersinia pestis can infect and survive within macrophages. However, the mechanisms that the bacterium use to subvert killing by these phagocytes have not been defined. To provide a better understanding of these mechanisms, we used an RNAi approach to identify host factors required for intracellular Y. pestis survival. This approach revealed that the host endocytic recycling pathway is essential for Y. pestis to avoid clearance by the macrophage. We further demonstrate that Y. pestis remodels the phagosome to resemble a recycling endosome, allowing the bacterium to avoid the normal phagolysosomal maturation pathway. Moreover, we show that infection with Y. pestis disrupts normal recycling in the macrophage and that disruption is required for bacterial replication. These findings provide the first evidence that Y. pestis targets the host endocytic recycling pathway in order to evade killing by macrophages.
format	article
author	Michael G. Connor Amanda R. Pulsifer Donghoon Chung Eric C. Rouchka Brian K. Ceresa Matthew B. Lawrenz
author_facet	Michael G. Connor Amanda R. Pulsifer Donghoon Chung Eric C. Rouchka Brian K. Ceresa Matthew B. Lawrenz
author_sort	Michael G. Connor
title	<italic toggle="yes">Yersinia pestis</italic> Targets the Host Endosome Recycling Pathway during the Biogenesis of the <italic toggle="yes">Yersinia</italic>-Containing Vacuole To Avoid Killing by Macrophages
title_short	<italic toggle="yes">Yersinia pestis</italic> Targets the Host Endosome Recycling Pathway during the Biogenesis of the <italic toggle="yes">Yersinia</italic>-Containing Vacuole To Avoid Killing by Macrophages
title_full	<italic toggle="yes">Yersinia pestis</italic> Targets the Host Endosome Recycling Pathway during the Biogenesis of the <italic toggle="yes">Yersinia</italic>-Containing Vacuole To Avoid Killing by Macrophages
title_fullStr	<italic toggle="yes">Yersinia pestis</italic> Targets the Host Endosome Recycling Pathway during the Biogenesis of the <italic toggle="yes">Yersinia</italic>-Containing Vacuole To Avoid Killing by Macrophages
title_full_unstemmed	<italic toggle="yes">Yersinia pestis</italic> Targets the Host Endosome Recycling Pathway during the Biogenesis of the <italic toggle="yes">Yersinia</italic>-Containing Vacuole To Avoid Killing by Macrophages
title_sort	<italic toggle="yes">yersinia pestis</italic> targets the host endosome recycling pathway during the biogenesis of the <italic toggle="yes">yersinia</italic>-containing vacuole to avoid killing by macrophages
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/ebf5230a7fe84bf694570a581c136c84
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<italic toggle="yes">Yersinia pestis</italic> Targets the Host Endosome Recycling Pathway during the Biogenesis of the <italic toggle="yes">Yersinia</italic>-Containing Vacuole To Avoid Killing by Macrophages

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