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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...
Autores principales: | , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2007
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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. |
format | Text |
id | pubmed-1924871 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2007 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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