<italic toggle="yes">cor</italic>, a Novel Carbon Monoxide Resistance Gene, Is Essential for <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Pathogenesis

ABSTRACT Tuberculosis, caused by Mycobacterium tuberculosis, remains a devastating human infectious disease, causing two million deaths annually. We previously demonstrated that M. tuberculosis induces an enzyme, heme oxygenase (HO1), that produces carbon monoxide (CO) gas and that M. tuberculosis a...

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Autores principales:	Vineetha M. Zacharia, Paolo S. Manzanillo, Vidhya R. Nair, Denise K. Marciano, Lisa N. Kinch, Nick V. Grishin, Jeffery S. Cox, Michael U. Shiloh
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2013
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1f534254f5d74508923b33aa7895a1f0
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spelling	oai:doaj.org-article:1f534254f5d74508923b33aa7895a1f02021-11-15T15:42:32Z<italic toggle="yes">cor</italic>, a Novel Carbon Monoxide Resistance Gene, Is Essential for <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Pathogenesis10.1128/mBio.00721-132150-7511https://doaj.org/article/1f534254f5d74508923b33aa7895a1f02013-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00721-13https://doaj.org/toc/2150-7511ABSTRACT Tuberculosis, caused by Mycobacterium tuberculosis, remains a devastating human infectious disease, causing two million deaths annually. We previously demonstrated that M. tuberculosis induces an enzyme, heme oxygenase (HO1), that produces carbon monoxide (CO) gas and that M. tuberculosis adapts its transcriptome during CO exposure. We now demonstrate that M. tuberculosis carries a novel resistance gene to combat CO toxicity. We screened an M. tuberculosis transposon library for CO-susceptible mutants and found that disruption of Rv1829 (carbon monoxide resistance, Cor) leads to marked CO sensitivity. Heterologous expression of Cor in Escherichia coli rescued it from CO toxicity. Importantly, the virulence of the cor mutant is attenuated in a mouse model of tuberculosis. Thus, Cor is necessary and sufficient to protect bacteria from host-derived CO. Taken together, this represents the first report of a role for HO1-derived CO in controlling infection of an intracellular pathogen and the first identification of a CO resistance gene in a pathogenic organism. IMPORTANCE Macrophages produce a variety of antimicrobial molecules, including nitric oxide (NO), hydrogen peroxide (H2O2), and acid (H+), that serve to kill engulfed bacteria. In addition to these molecules, human and mouse macrophages also produce carbon monoxide (CO) gas by the heme oxygenase (HO1) enzyme. We observed that, in contrast to other bacteria, mycobacteria are resistant to CO, suggesting that this might be an evolutionary adaptation of mycobacteria for survival within macrophages. We screened a panel of ~2,500 M. tuberculosis mutants to determine which genes are required for survival of M. tuberculosis in the presence of CO. Within this panel, we identified one such gene, cor, that specifically confers CO resistance. Importantly, we found that the ability of M. tuberculosis cells carrying a mutated copy of this gene to cause tuberculosis in a mouse disease model is significantly attenuated. This indicates that CO resistance is essential for mycobacterial survival in vivo.Vineetha M. ZachariaPaolo S. ManzanilloVidhya R. NairDenise K. MarcianoLisa N. KinchNick V. GrishinJeffery S. CoxMichael U. ShilohAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 4, Iss 6 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Vineetha M. Zacharia Paolo S. Manzanillo Vidhya R. Nair Denise K. Marciano Lisa N. Kinch Nick V. Grishin Jeffery S. Cox Michael U. Shiloh <italic toggle="yes">cor</italic>, a Novel Carbon Monoxide Resistance Gene, Is Essential for <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Pathogenesis
description	ABSTRACT Tuberculosis, caused by Mycobacterium tuberculosis, remains a devastating human infectious disease, causing two million deaths annually. We previously demonstrated that M. tuberculosis induces an enzyme, heme oxygenase (HO1), that produces carbon monoxide (CO) gas and that M. tuberculosis adapts its transcriptome during CO exposure. We now demonstrate that M. tuberculosis carries a novel resistance gene to combat CO toxicity. We screened an M. tuberculosis transposon library for CO-susceptible mutants and found that disruption of Rv1829 (carbon monoxide resistance, Cor) leads to marked CO sensitivity. Heterologous expression of Cor in Escherichia coli rescued it from CO toxicity. Importantly, the virulence of the cor mutant is attenuated in a mouse model of tuberculosis. Thus, Cor is necessary and sufficient to protect bacteria from host-derived CO. Taken together, this represents the first report of a role for HO1-derived CO in controlling infection of an intracellular pathogen and the first identification of a CO resistance gene in a pathogenic organism. IMPORTANCE Macrophages produce a variety of antimicrobial molecules, including nitric oxide (NO), hydrogen peroxide (H2O2), and acid (H+), that serve to kill engulfed bacteria. In addition to these molecules, human and mouse macrophages also produce carbon monoxide (CO) gas by the heme oxygenase (HO1) enzyme. We observed that, in contrast to other bacteria, mycobacteria are resistant to CO, suggesting that this might be an evolutionary adaptation of mycobacteria for survival within macrophages. We screened a panel of ~2,500 M. tuberculosis mutants to determine which genes are required for survival of M. tuberculosis in the presence of CO. Within this panel, we identified one such gene, cor, that specifically confers CO resistance. Importantly, we found that the ability of M. tuberculosis cells carrying a mutated copy of this gene to cause tuberculosis in a mouse disease model is significantly attenuated. This indicates that CO resistance is essential for mycobacterial survival in vivo.
format	article
author	Vineetha M. Zacharia Paolo S. Manzanillo Vidhya R. Nair Denise K. Marciano Lisa N. Kinch Nick V. Grishin Jeffery S. Cox Michael U. Shiloh
author_facet	Vineetha M. Zacharia Paolo S. Manzanillo Vidhya R. Nair Denise K. Marciano Lisa N. Kinch Nick V. Grishin Jeffery S. Cox Michael U. Shiloh
author_sort	Vineetha M. Zacharia
title	<italic toggle="yes">cor</italic>, a Novel Carbon Monoxide Resistance Gene, Is Essential for <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Pathogenesis
title_short	<italic toggle="yes">cor</italic>, a Novel Carbon Monoxide Resistance Gene, Is Essential for <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Pathogenesis
title_full	<italic toggle="yes">cor</italic>, a Novel Carbon Monoxide Resistance Gene, Is Essential for <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Pathogenesis
title_fullStr	<italic toggle="yes">cor</italic>, a Novel Carbon Monoxide Resistance Gene, Is Essential for <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Pathogenesis
title_full_unstemmed	<italic toggle="yes">cor</italic>, a Novel Carbon Monoxide Resistance Gene, Is Essential for <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Pathogenesis
title_sort	<italic toggle="yes">cor</italic>, a novel carbon monoxide resistance gene, is essential for <named-content content-type="genus-species">mycobacterium tuberculosis</named-content> pathogenesis
publisher	American Society for Microbiology
publishDate	2013
url	https://doaj.org/article/1f534254f5d74508923b33aa7895a1f0
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<italic toggle="yes">cor</italic>, a Novel Carbon Monoxide Resistance Gene, Is Essential for <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Pathogenesis

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