The Capacity of <italic toggle="yes">Mycobacterium tuberculosis</italic> To Survive Iron Starvation Might Enable It To Persist in Iron-Deprived Microenvironments of Human Granulomas

ABSTRACT This study was conducted to investigate the role of iron deprivation in the persistence of Mycobacterium tuberculosis. We present evidence of iron restriction in human necrotic granulomas and demonstrate that under iron starvation M. tuberculosis persists, refractive to antibiotics and capa...

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Autores principales:	Krishna Kurthkoti, Hamel Amin, Mohlopheni J. Marakalala, Saleena Ghanny, Selvakumar Subbian, Alexandra Sakatos, Jonathan Livny, Sarah M. Fortune, Michael Berney, G. Marcela Rodriguez
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Mycobacterium tuberculosis TB granuloma iron acquisition iron deprivation iron sequestration latent TB Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9ea9094635ae48e2a25c39feefe73d81
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spelling	oai:doaj.org-article:9ea9094635ae48e2a25c39feefe73d812021-11-15T15:51:43ZThe Capacity of <italic toggle="yes">Mycobacterium tuberculosis</italic> To Survive Iron Starvation Might Enable It To Persist in Iron-Deprived Microenvironments of Human Granulomas10.1128/mBio.01092-172150-7511https://doaj.org/article/9ea9094635ae48e2a25c39feefe73d812017-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01092-17https://doaj.org/toc/2150-7511ABSTRACT This study was conducted to investigate the role of iron deprivation in the persistence of Mycobacterium tuberculosis. We present evidence of iron restriction in human necrotic granulomas and demonstrate that under iron starvation M. tuberculosis persists, refractive to antibiotics and capable of restarting replication when iron is made available. Transcriptomics and metabolomic analyses indicated that the persistence of M. tuberculosis under iron starvation is dependent on strict control of endogenous Fe utilization and is associated with upregulation of pathogenicity and intrinsic antibiotic resistance determinants. M. tuberculosis mutants compromised in their ability to survive Fe starvation were identified. The findings of this study advance the understanding of the physiological settings that may underpin the chronicity of human tuberculosis (TB) and are relevant to the design of effective antitubercular therapies. IMPORTANCE One-third of the world population may harbor persistent M. tuberculosis, causing an asymptomatic infection that is refractory to treatment and can reactivate to become potentially lethal tuberculosis disease. However, little is known about the factors that trigger and maintain M. tuberculosis persistence in infected individuals. Iron is an essential nutrient for M. tuberculosis growth. In this study, we show, first, that in human granulomas the immune defense creates microenvironments in which M. tuberculosis likely experiences drastic Fe deprivation and, second, that Fe-starved M. tuberculosis is capable of long-term persistence without growth. Together, these observations suggest that Fe deprivation in the lung might trigger a state of persistence in M. tuberculosis and promote chronic TB. We also identified vulnerabilities of iron-restricted persistent M. tuberculosis, which can be exploited for the design of new antitubercular therapies.Krishna KurthkotiHamel AminMohlopheni J. MarakalalaSaleena GhannySelvakumar SubbianAlexandra SakatosJonathan LivnySarah M. FortuneMichael BerneyG. Marcela RodriguezAmerican Society for MicrobiologyarticleMycobacterium tuberculosisTB granulomairon acquisitioniron deprivationiron sequestrationlatent TBMicrobiologyQR1-502ENmBio, Vol 8, Iss 4 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Mycobacterium tuberculosis TB granuloma iron acquisition iron deprivation iron sequestration latent TB Microbiology QR1-502
spellingShingle	Mycobacterium tuberculosis TB granuloma iron acquisition iron deprivation iron sequestration latent TB Microbiology QR1-502 Krishna Kurthkoti Hamel Amin Mohlopheni J. Marakalala Saleena Ghanny Selvakumar Subbian Alexandra Sakatos Jonathan Livny Sarah M. Fortune Michael Berney G. Marcela Rodriguez The Capacity of <italic toggle="yes">Mycobacterium tuberculosis</italic> To Survive Iron Starvation Might Enable It To Persist in Iron-Deprived Microenvironments of Human Granulomas
description	ABSTRACT This study was conducted to investigate the role of iron deprivation in the persistence of Mycobacterium tuberculosis. We present evidence of iron restriction in human necrotic granulomas and demonstrate that under iron starvation M. tuberculosis persists, refractive to antibiotics and capable of restarting replication when iron is made available. Transcriptomics and metabolomic analyses indicated that the persistence of M. tuberculosis under iron starvation is dependent on strict control of endogenous Fe utilization and is associated with upregulation of pathogenicity and intrinsic antibiotic resistance determinants. M. tuberculosis mutants compromised in their ability to survive Fe starvation were identified. The findings of this study advance the understanding of the physiological settings that may underpin the chronicity of human tuberculosis (TB) and are relevant to the design of effective antitubercular therapies. IMPORTANCE One-third of the world population may harbor persistent M. tuberculosis, causing an asymptomatic infection that is refractory to treatment and can reactivate to become potentially lethal tuberculosis disease. However, little is known about the factors that trigger and maintain M. tuberculosis persistence in infected individuals. Iron is an essential nutrient for M. tuberculosis growth. In this study, we show, first, that in human granulomas the immune defense creates microenvironments in which M. tuberculosis likely experiences drastic Fe deprivation and, second, that Fe-starved M. tuberculosis is capable of long-term persistence without growth. Together, these observations suggest that Fe deprivation in the lung might trigger a state of persistence in M. tuberculosis and promote chronic TB. We also identified vulnerabilities of iron-restricted persistent M. tuberculosis, which can be exploited for the design of new antitubercular therapies.
format	article
author	Krishna Kurthkoti Hamel Amin Mohlopheni J. Marakalala Saleena Ghanny Selvakumar Subbian Alexandra Sakatos Jonathan Livny Sarah M. Fortune Michael Berney G. Marcela Rodriguez
author_facet	Krishna Kurthkoti Hamel Amin Mohlopheni J. Marakalala Saleena Ghanny Selvakumar Subbian Alexandra Sakatos Jonathan Livny Sarah M. Fortune Michael Berney G. Marcela Rodriguez
author_sort	Krishna Kurthkoti
title	The Capacity of <italic toggle="yes">Mycobacterium tuberculosis</italic> To Survive Iron Starvation Might Enable It To Persist in Iron-Deprived Microenvironments of Human Granulomas
title_short	The Capacity of <italic toggle="yes">Mycobacterium tuberculosis</italic> To Survive Iron Starvation Might Enable It To Persist in Iron-Deprived Microenvironments of Human Granulomas
title_full	The Capacity of <italic toggle="yes">Mycobacterium tuberculosis</italic> To Survive Iron Starvation Might Enable It To Persist in Iron-Deprived Microenvironments of Human Granulomas
title_fullStr	The Capacity of <italic toggle="yes">Mycobacterium tuberculosis</italic> To Survive Iron Starvation Might Enable It To Persist in Iron-Deprived Microenvironments of Human Granulomas
title_full_unstemmed	The Capacity of <italic toggle="yes">Mycobacterium tuberculosis</italic> To Survive Iron Starvation Might Enable It To Persist in Iron-Deprived Microenvironments of Human Granulomas
title_sort	capacity of <italic toggle="yes">mycobacterium tuberculosis</italic> to survive iron starvation might enable it to persist in iron-deprived microenvironments of human granulomas
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/9ea9094635ae48e2a25c39feefe73d81
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The Capacity of <italic toggle="yes">Mycobacterium tuberculosis</italic> To Survive Iron Starvation Might Enable It To Persist in Iron-Deprived Microenvironments of Human Granulomas

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