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Mycobacterium tuberculosis nuoG Is a Virulence Gene That Inhibits Apoptosis of Infected Host Cells

The survival and persistence of Mycobacterium tuberculosis depends on its capacity to manipulate multiple host defense pathways, including the ability to actively inhibit the death by apoptosis of infected host cells. The genetic basis for this anti-apoptotic activity and its implication for mycobac...

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Autores principales: Velmurugan, Kamalakannan, Chen, Bing, Miller, Jessica L, Azogue, Sharon, Gurses, Serdar, Hsu, Tsungda, Glickman, Michael, Jacobs, William R, Porcelli, Steven A, Briken, Volker
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1924871/
https://www.ncbi.nlm.nih.gov/pubmed/17658950
http://dx.doi.org/10.1371/journal.ppat.0030110
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author Velmurugan, Kamalakannan
Chen, Bing
Miller, Jessica L
Azogue, Sharon
Gurses, Serdar
Hsu, Tsungda
Glickman, Michael
Jacobs, William R
Porcelli, Steven A
Briken, Volker
author_facet Velmurugan, Kamalakannan
Chen, Bing
Miller, Jessica L
Azogue, Sharon
Gurses, Serdar
Hsu, Tsungda
Glickman, Michael
Jacobs, William R
Porcelli, Steven A
Briken, Volker
author_sort Velmurugan, Kamalakannan
collection PubMed
description The survival and persistence of Mycobacterium tuberculosis depends on its capacity to manipulate multiple host defense pathways, including the ability to actively inhibit the death by apoptosis of infected host cells. The genetic basis for this anti-apoptotic activity and its implication for mycobacterial virulence have not been demonstrated or elucidated. Using a novel gain-of-function genetic screen, we demonstrated that inhibition of infection-induced apoptosis of macrophages is controlled by multiple genetic loci in M. tuberculosis. Characterization of one of these loci in detail revealed that the anti-apoptosis activity was attributable to the type I NADH-dehydrogenase of M. tuberculosis, and was mainly due to the subunit of this multicomponent complex encoded by the nuoG gene. Expression of M. tuberculosis nuoG in nonpathogenic mycobacteria endowed them with the ability to inhibit apoptosis of infected human or mouse macrophages, and increased their virulence in a SCID mouse model. Conversely, deletion of nuoG in M. tuberculosis ablated its ability to inhibit macrophage apoptosis and significantly reduced its virulence in mice. These results identify a key component of the genetic basis for an important virulence trait of M. tuberculosis and support a direct causal relationship between virulence of pathogenic mycobacteria and their ability to inhibit macrophage apoptosis.
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spelling pubmed-19248712007-07-26 Mycobacterium tuberculosis nuoG Is a Virulence Gene That Inhibits Apoptosis of Infected Host Cells Velmurugan, Kamalakannan Chen, Bing Miller, Jessica L Azogue, Sharon Gurses, Serdar Hsu, Tsungda Glickman, Michael Jacobs, William R Porcelli, Steven A Briken, Volker PLoS Pathog Research Article The survival and persistence of Mycobacterium tuberculosis depends on its capacity to manipulate multiple host defense pathways, including the ability to actively inhibit the death by apoptosis of infected host cells. The genetic basis for this anti-apoptotic activity and its implication for mycobacterial virulence have not been demonstrated or elucidated. Using a novel gain-of-function genetic screen, we demonstrated that inhibition of infection-induced apoptosis of macrophages is controlled by multiple genetic loci in M. tuberculosis. Characterization of one of these loci in detail revealed that the anti-apoptosis activity was attributable to the type I NADH-dehydrogenase of M. tuberculosis, and was mainly due to the subunit of this multicomponent complex encoded by the nuoG gene. Expression of M. tuberculosis nuoG in nonpathogenic mycobacteria endowed them with the ability to inhibit apoptosis of infected human or mouse macrophages, and increased their virulence in a SCID mouse model. Conversely, deletion of nuoG in M. tuberculosis ablated its ability to inhibit macrophage apoptosis and significantly reduced its virulence in mice. These results identify a key component of the genetic basis for an important virulence trait of M. tuberculosis and support a direct causal relationship between virulence of pathogenic mycobacteria and their ability to inhibit macrophage apoptosis. Public Library of Science 2007-07 2007-07-20 /pmc/articles/PMC1924871/ /pubmed/17658950 http://dx.doi.org/10.1371/journal.ppat.0030110 Text en © 2007 Velmurugan 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
Velmurugan, Kamalakannan
Chen, Bing
Miller, Jessica L
Azogue, Sharon
Gurses, Serdar
Hsu, Tsungda
Glickman, Michael
Jacobs, William R
Porcelli, Steven A
Briken, Volker
Mycobacterium tuberculosis nuoG Is a Virulence Gene That Inhibits Apoptosis of Infected Host Cells
title Mycobacterium tuberculosis nuoG Is a Virulence Gene That Inhibits Apoptosis of Infected Host Cells
title_full Mycobacterium tuberculosis nuoG Is a Virulence Gene That Inhibits Apoptosis of Infected Host Cells
title_fullStr Mycobacterium tuberculosis nuoG Is a Virulence Gene That Inhibits Apoptosis of Infected Host Cells
title_full_unstemmed Mycobacterium tuberculosis nuoG Is a Virulence Gene That Inhibits Apoptosis of Infected Host Cells
title_short Mycobacterium tuberculosis nuoG Is a Virulence Gene That Inhibits Apoptosis of Infected Host Cells
title_sort mycobacterium tuberculosis nuog is a virulence gene that inhibits apoptosis of infected host cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1924871/
https://www.ncbi.nlm.nih.gov/pubmed/17658950
http://dx.doi.org/10.1371/journal.ppat.0030110
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