Host factors required for modulation of phagosome biogenesis and proliferation of Francisella tularensis within the cytosol.

Francisella tularensis is a highly infectious facultative intracellular bacterium that can be transmitted between mammals by arthropod vectors. Similar to many other intracellular bacteria that replicate within the cytosol, such as Listeria, Shigella, Burkholderia, and Rickettsia, the virulence of F...

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Autores principales:	Christine Akimana, Souhaila Al-Khodor, Yousef Abu Kwaik
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9bafef05c9484f65952211fb6f3546f9
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spelling	oai:doaj.org-article:9bafef05c9484f65952211fb6f3546f92021-12-02T20:21:00ZHost factors required for modulation of phagosome biogenesis and proliferation of Francisella tularensis within the cytosol.1932-620310.1371/journal.pone.0011025https://doaj.org/article/9bafef05c9484f65952211fb6f3546f92010-06-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20552012/?tool=EBIhttps://doaj.org/toc/1932-6203Francisella tularensis is a highly infectious facultative intracellular bacterium that can be transmitted between mammals by arthropod vectors. Similar to many other intracellular bacteria that replicate within the cytosol, such as Listeria, Shigella, Burkholderia, and Rickettsia, the virulence of F. tularensis depends on its ability to modulate biogenesis of its phagosome and to escape into the host cell cytosol where it proliferates. Recent studies have identified the F. tularensis genes required for modulation of phagosome biogenesis and escape into the host cell cytosol within human and arthropod-derived cells. However, the arthropod and mammalian host factors required for intracellular proliferation of F. tularensis are not known. We have utilized a forward genetic approach employing genome-wide RNAi screen in Drosophila melanogaster-derived cells. Screening a library of approximately 21,300 RNAi, we have identified at least 186 host factors required for intracellular bacterial proliferation. We silenced twelve mammalian homologues by RNAi in HEK293T cells and identified three conserved factors, the PI4 kinase PI4KCA, the ubiquitin hydrolase USP22, and the ubiquitin ligase CDC27, which are also required for replication in human cells. The PI4KCA and USP22 mammalian factors are not required for modulation of phagosome biogenesis or phagosomal escape but are required for proliferation within the cytosol. In contrast, the CDC27 ubiquitin ligase is required for evading lysosomal fusion and for phagosomal escape into the cytosol. Although F. tularensis interacts with the autophagy pathway during late stages of proliferation in mouse macrophages, this does not occur in human cells. Our data suggest that F. tularensis utilizes host ubiquitin turnover in distinct mechanisms during the phagosomal and cytosolic phases and phosphoinositide metabolism is essential for cytosolic proliferation of F. tularensis. Our data will facilitate deciphering molecular ecology, patho-adaptation of F. tularensis to the arthropod vector and its role in bacterial ecology and patho-evolution to infect mammals.Christine AkimanaSouhaila Al-KhodorYousef Abu KwaikPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 6, p e11025 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Christine Akimana Souhaila Al-Khodor Yousef Abu Kwaik Host factors required for modulation of phagosome biogenesis and proliferation of Francisella tularensis within the cytosol.
description	Francisella tularensis is a highly infectious facultative intracellular bacterium that can be transmitted between mammals by arthropod vectors. Similar to many other intracellular bacteria that replicate within the cytosol, such as Listeria, Shigella, Burkholderia, and Rickettsia, the virulence of F. tularensis depends on its ability to modulate biogenesis of its phagosome and to escape into the host cell cytosol where it proliferates. Recent studies have identified the F. tularensis genes required for modulation of phagosome biogenesis and escape into the host cell cytosol within human and arthropod-derived cells. However, the arthropod and mammalian host factors required for intracellular proliferation of F. tularensis are not known. We have utilized a forward genetic approach employing genome-wide RNAi screen in Drosophila melanogaster-derived cells. Screening a library of approximately 21,300 RNAi, we have identified at least 186 host factors required for intracellular bacterial proliferation. We silenced twelve mammalian homologues by RNAi in HEK293T cells and identified three conserved factors, the PI4 kinase PI4KCA, the ubiquitin hydrolase USP22, and the ubiquitin ligase CDC27, which are also required for replication in human cells. The PI4KCA and USP22 mammalian factors are not required for modulation of phagosome biogenesis or phagosomal escape but are required for proliferation within the cytosol. In contrast, the CDC27 ubiquitin ligase is required for evading lysosomal fusion and for phagosomal escape into the cytosol. Although F. tularensis interacts with the autophagy pathway during late stages of proliferation in mouse macrophages, this does not occur in human cells. Our data suggest that F. tularensis utilizes host ubiquitin turnover in distinct mechanisms during the phagosomal and cytosolic phases and phosphoinositide metabolism is essential for cytosolic proliferation of F. tularensis. Our data will facilitate deciphering molecular ecology, patho-adaptation of F. tularensis to the arthropod vector and its role in bacterial ecology and patho-evolution to infect mammals.
format	article
author	Christine Akimana Souhaila Al-Khodor Yousef Abu Kwaik
author_facet	Christine Akimana Souhaila Al-Khodor Yousef Abu Kwaik
author_sort	Christine Akimana
title	Host factors required for modulation of phagosome biogenesis and proliferation of Francisella tularensis within the cytosol.
title_short	Host factors required for modulation of phagosome biogenesis and proliferation of Francisella tularensis within the cytosol.
title_full	Host factors required for modulation of phagosome biogenesis and proliferation of Francisella tularensis within the cytosol.
title_fullStr	Host factors required for modulation of phagosome biogenesis and proliferation of Francisella tularensis within the cytosol.
title_full_unstemmed	Host factors required for modulation of phagosome biogenesis and proliferation of Francisella tularensis within the cytosol.
title_sort	host factors required for modulation of phagosome biogenesis and proliferation of francisella tularensis within the cytosol.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/9bafef05c9484f65952211fb6f3546f9
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Host factors required for modulation of phagosome biogenesis and proliferation of Francisella tularensis within the cytosol.

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