The Cell Wall Lipid PDIM Contributes to Phagosomal Escape and Host Cell Exit of <italic toggle="yes">Mycobacterium tuberculosis</italic>

ABSTRACT The cell wall of Mycobacterium tuberculosis is composed of unique lipids that are important for pathogenesis. Indeed, the first-ever genetic screen in M. tuberculosis identified genes involved in the biosynthesis and transport of the cell wall lipid PDIM (phthiocerol dimycocerosates) as cru...

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Autores principales:	Jeff Quigley, V. Keith Hughitt, Carlos A. Velikovsky, Roy A. Mariuzza, Najib M. El-Sayed, Volker Briken
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0e3bad085cc34cf9b1eece179b714cd2
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spelling	oai:doaj.org-article:0e3bad085cc34cf9b1eece179b714cd22021-11-15T15:50:59ZThe Cell Wall Lipid PDIM Contributes to Phagosomal Escape and Host Cell Exit of <italic toggle="yes">Mycobacterium tuberculosis</italic>10.1128/mBio.00148-172150-7511https://doaj.org/article/0e3bad085cc34cf9b1eece179b714cd22017-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00148-17https://doaj.org/toc/2150-7511ABSTRACT The cell wall of Mycobacterium tuberculosis is composed of unique lipids that are important for pathogenesis. Indeed, the first-ever genetic screen in M. tuberculosis identified genes involved in the biosynthesis and transport of the cell wall lipid PDIM (phthiocerol dimycocerosates) as crucial for the survival of M. tuberculosis in mice. Here we show evidence for a novel molecular mechanism of the PDIM-mediated virulence in M. tuberculosis. We characterized the DNA interaction and the regulon of Rv3167c, a transcriptional repressor that is involved in virulence regulation of M. tuberculosis, and discovered that it controls the PDIM operon. A loss-of-function genetic approach showed that PDIM levels directly correlate with the capacity of M. tuberculosis to escape the phagosome and induce host cell necrosis and macroautophagy. In conclusion, our study attributes a novel role of the cell wall lipid PDIM in intracellular host cell modulation, which is important for host cell exit and dissemination of M. tuberculosis. IMPORTANCE Mycobacterium tuberculosis is a major human pathogen that has coevolved with its host for thousands of years. The complex and unique cell wall of M. tuberculosis contains the lipid PDIM (phthiocerol dimycocerosates), which is crucial for virulence of the bacterium, but its function is not well understood. Here we show that PDIM expression by M. tuberculosis is negatively regulated by a novel transcriptional repressor, Rv3167c. In addition, we discovered that the escape of M. tuberculosis from its intracellular vacuole was greatly augmented by the presence of PDIM. The increased release of M. tuberculosis into the cytosol led to increased host cell necrosis. The discovery of a link between the cell wall lipid PDIM and a major pathogenesis pathway of M. tuberculosis provides important insights into the molecular mechanisms of host cell manipulation by M. tuberculosis.Jeff QuigleyV. Keith HughittCarlos A. VelikovskyRoy A. MariuzzaNajib M. El-SayedVolker BrikenAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 8, Iss 2 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Jeff Quigley V. Keith Hughitt Carlos A. Velikovsky Roy A. Mariuzza Najib M. El-Sayed Volker Briken The Cell Wall Lipid PDIM Contributes to Phagosomal Escape and Host Cell Exit of <italic toggle="yes">Mycobacterium tuberculosis</italic>
description	ABSTRACT The cell wall of Mycobacterium tuberculosis is composed of unique lipids that are important for pathogenesis. Indeed, the first-ever genetic screen in M. tuberculosis identified genes involved in the biosynthesis and transport of the cell wall lipid PDIM (phthiocerol dimycocerosates) as crucial for the survival of M. tuberculosis in mice. Here we show evidence for a novel molecular mechanism of the PDIM-mediated virulence in M. tuberculosis. We characterized the DNA interaction and the regulon of Rv3167c, a transcriptional repressor that is involved in virulence regulation of M. tuberculosis, and discovered that it controls the PDIM operon. A loss-of-function genetic approach showed that PDIM levels directly correlate with the capacity of M. tuberculosis to escape the phagosome and induce host cell necrosis and macroautophagy. In conclusion, our study attributes a novel role of the cell wall lipid PDIM in intracellular host cell modulation, which is important for host cell exit and dissemination of M. tuberculosis. IMPORTANCE Mycobacterium tuberculosis is a major human pathogen that has coevolved with its host for thousands of years. The complex and unique cell wall of M. tuberculosis contains the lipid PDIM (phthiocerol dimycocerosates), which is crucial for virulence of the bacterium, but its function is not well understood. Here we show that PDIM expression by M. tuberculosis is negatively regulated by a novel transcriptional repressor, Rv3167c. In addition, we discovered that the escape of M. tuberculosis from its intracellular vacuole was greatly augmented by the presence of PDIM. The increased release of M. tuberculosis into the cytosol led to increased host cell necrosis. The discovery of a link between the cell wall lipid PDIM and a major pathogenesis pathway of M. tuberculosis provides important insights into the molecular mechanisms of host cell manipulation by M. tuberculosis.
format	article
author	Jeff Quigley V. Keith Hughitt Carlos A. Velikovsky Roy A. Mariuzza Najib M. El-Sayed Volker Briken
author_facet	Jeff Quigley V. Keith Hughitt Carlos A. Velikovsky Roy A. Mariuzza Najib M. El-Sayed Volker Briken
author_sort	Jeff Quigley
title	The Cell Wall Lipid PDIM Contributes to Phagosomal Escape and Host Cell Exit of <italic toggle="yes">Mycobacterium tuberculosis</italic>
title_short	The Cell Wall Lipid PDIM Contributes to Phagosomal Escape and Host Cell Exit of <italic toggle="yes">Mycobacterium tuberculosis</italic>
title_full	The Cell Wall Lipid PDIM Contributes to Phagosomal Escape and Host Cell Exit of <italic toggle="yes">Mycobacterium tuberculosis</italic>
title_fullStr	The Cell Wall Lipid PDIM Contributes to Phagosomal Escape and Host Cell Exit of <italic toggle="yes">Mycobacterium tuberculosis</italic>
title_full_unstemmed	The Cell Wall Lipid PDIM Contributes to Phagosomal Escape and Host Cell Exit of <italic toggle="yes">Mycobacterium tuberculosis</italic>
title_sort	cell wall lipid pdim contributes to phagosomal escape and host cell exit of <italic toggle="yes">mycobacterium tuberculosis</italic>
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/0e3bad085cc34cf9b1eece179b714cd2
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The Cell Wall Lipid PDIM Contributes to Phagosomal Escape and Host Cell Exit of <italic toggle="yes">Mycobacterium tuberculosis</italic>

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