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Identification of a Transcription Factor That Regulates Host Cell Exit and Virulence of Mycobacterium tuberculosis

The interaction of Mycobacterium tuberculosis (Mtb) with host cell death signaling pathways is characterized by an initial anti-apoptotic phase followed by a pro-necrotic phase to allow for host cell exit of the bacteria. The bacterial modulators regulating necrosis induction are poorly understood....

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Autores principales: Srinivasan, Lalitha, Gurses, Serdar A., Hurley, Benjamin E., Miller, Jessica L., Karakousis, Petros C., Briken, Volker
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871555/
https://www.ncbi.nlm.nih.gov/pubmed/27191591
http://dx.doi.org/10.1371/journal.ppat.1005652
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author Srinivasan, Lalitha
Gurses, Serdar A.
Hurley, Benjamin E.
Miller, Jessica L.
Karakousis, Petros C.
Briken, Volker
author_facet Srinivasan, Lalitha
Gurses, Serdar A.
Hurley, Benjamin E.
Miller, Jessica L.
Karakousis, Petros C.
Briken, Volker
author_sort Srinivasan, Lalitha
collection PubMed
description The interaction of Mycobacterium tuberculosis (Mtb) with host cell death signaling pathways is characterized by an initial anti-apoptotic phase followed by a pro-necrotic phase to allow for host cell exit of the bacteria. The bacterial modulators regulating necrosis induction are poorly understood. Here we describe the identification of a transcriptional repressor, Rv3167c responsible for regulating the escape of Mtb from the phagosome. Increased cytosolic localization of MtbΔRv3167c was accompanied by elevated levels of mitochondrial reactive oxygen species and reduced activation of the protein kinase Akt, and these events were critical for the induction of host cell necrosis and macroautophagy. The increase in necrosis led to an increase in bacterial virulence as reflected in higher bacterial burden and reduced survival of mice infected with MtbΔRv3167c. The regulon of Rv3167c thus contains the bacterial mediators involved in escape from the phagosome and host cell necrosis induction, both of which are crucial steps in the intracellular lifecycle and virulence of Mtb.
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spelling pubmed-48715552016-05-31 Identification of a Transcription Factor That Regulates Host Cell Exit and Virulence of Mycobacterium tuberculosis Srinivasan, Lalitha Gurses, Serdar A. Hurley, Benjamin E. Miller, Jessica L. Karakousis, Petros C. Briken, Volker PLoS Pathog Research Article The interaction of Mycobacterium tuberculosis (Mtb) with host cell death signaling pathways is characterized by an initial anti-apoptotic phase followed by a pro-necrotic phase to allow for host cell exit of the bacteria. The bacterial modulators regulating necrosis induction are poorly understood. Here we describe the identification of a transcriptional repressor, Rv3167c responsible for regulating the escape of Mtb from the phagosome. Increased cytosolic localization of MtbΔRv3167c was accompanied by elevated levels of mitochondrial reactive oxygen species and reduced activation of the protein kinase Akt, and these events were critical for the induction of host cell necrosis and macroautophagy. The increase in necrosis led to an increase in bacterial virulence as reflected in higher bacterial burden and reduced survival of mice infected with MtbΔRv3167c. The regulon of Rv3167c thus contains the bacterial mediators involved in escape from the phagosome and host cell necrosis induction, both of which are crucial steps in the intracellular lifecycle and virulence of Mtb. Public Library of Science 2016-05-18 /pmc/articles/PMC4871555/ /pubmed/27191591 http://dx.doi.org/10.1371/journal.ppat.1005652 Text en © 2016 Srinivasan et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Srinivasan, Lalitha
Gurses, Serdar A.
Hurley, Benjamin E.
Miller, Jessica L.
Karakousis, Petros C.
Briken, Volker
Identification of a Transcription Factor That Regulates Host Cell Exit and Virulence of Mycobacterium tuberculosis
title Identification of a Transcription Factor That Regulates Host Cell Exit and Virulence of Mycobacterium tuberculosis
title_full Identification of a Transcription Factor That Regulates Host Cell Exit and Virulence of Mycobacterium tuberculosis
title_fullStr Identification of a Transcription Factor That Regulates Host Cell Exit and Virulence of Mycobacterium tuberculosis
title_full_unstemmed Identification of a Transcription Factor That Regulates Host Cell Exit and Virulence of Mycobacterium tuberculosis
title_short Identification of a Transcription Factor That Regulates Host Cell Exit and Virulence of Mycobacterium tuberculosis
title_sort identification of a transcription factor that regulates host cell exit and virulence of mycobacterium tuberculosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871555/
https://www.ncbi.nlm.nih.gov/pubmed/27191591
http://dx.doi.org/10.1371/journal.ppat.1005652
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