The capacity of mycobacterium tuberculosis to survive iron starvation might enable it to persist in iron- deprived microenvironments of human granulomas

Krishna Kurthkoti, Hamel Amin, Mohlopheni J. Marakalala, Saleena Ghanny, Selvakumar Subbian, Alexandra Sakatos, Jonathan Livny, Sarah M. Fortune, Michael Berney, G. Marcela Rodriguez

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere01092-17
JournalmBio
Volume8
Issue number4
DOIs
StatePublished - Jul 1 2017

Fingerprint

Starvation
Granuloma
Mycobacterium tuberculosis
Iron
Tuberculosis
Asymptomatic Infections
Metabolomics
Microbial Drug Resistance
Growth
Virulence
Up-Regulation
Anti-Bacterial Agents
Food
Lung

Keywords

  • Iron acquisition
  • Iron deprivation
  • Iron sequestration
  • Latent TB
  • Mycobacterium tuberculosis
  • Nutritional immunity
  • Persistence
  • TB granuloma

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Kurthkoti, K., Amin, H., Marakalala, M. J., Ghanny, S., Subbian, S., Sakatos, A., ... Rodriguez, G. M. (2017). The capacity of mycobacterium tuberculosis to survive iron starvation might enable it to persist in iron- deprived microenvironments of human granulomas. mBio, 8(4), [e01092-17]. https://doi.org/10.1128/mBio.01092-17

The capacity of mycobacterium tuberculosis to survive iron starvation might enable it to persist in iron- deprived microenvironments of human granulomas. / Kurthkoti, Krishna; Amin, Hamel; Marakalala, Mohlopheni J.; Ghanny, Saleena; Subbian, Selvakumar; Sakatos, Alexandra; Livny, Jonathan; Fortune, Sarah M.; Berney, Michael; Rodriguez, G. Marcela.

In: mBio, Vol. 8, No. 4, e01092-17, 01.07.2017.

Research output: Contribution to journalArticle

Kurthkoti, K, Amin, H, Marakalala, MJ, Ghanny, S, Subbian, S, Sakatos, A, Livny, J, Fortune, SM, Berney, M & Rodriguez, GM 2017, 'The capacity of mycobacterium tuberculosis to survive iron starvation might enable it to persist in iron- deprived microenvironments of human granulomas', mBio, vol. 8, no. 4, e01092-17. https://doi.org/10.1128/mBio.01092-17
Kurthkoti, Krishna ; Amin, Hamel ; Marakalala, Mohlopheni J. ; Ghanny, Saleena ; Subbian, Selvakumar ; Sakatos, Alexandra ; Livny, Jonathan ; Fortune, Sarah M. ; Berney, Michael ; Rodriguez, G. Marcela. / The capacity of mycobacterium tuberculosis to survive iron starvation might enable it to persist in iron- deprived microenvironments of human granulomas. In: mBio. 2017 ; Vol. 8, No. 4.
@article{8d6e634863f740c198d662e0b1d4b214,
title = "The capacity of mycobacterium tuberculosis 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 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.",
keywords = "Iron acquisition, Iron deprivation, Iron sequestration, Latent TB, Mycobacterium tuberculosis, Nutritional immunity, Persistence, TB granuloma",
author = "Krishna Kurthkoti and Hamel Amin and Marakalala, {Mohlopheni J.} and Saleena Ghanny and Selvakumar Subbian and Alexandra Sakatos and Jonathan Livny and Fortune, {Sarah M.} and Michael Berney and Rodriguez, {G. Marcela}",
year = "2017",
month = "7",
day = "1",
doi = "10.1128/mBio.01092-17",
language = "English (US)",
volume = "8",
journal = "mBio",
issn = "2161-2129",
publisher = "American Society for Microbiology",
number = "4",

}

TY - JOUR

T1 - The capacity of mycobacterium tuberculosis to survive iron starvation might enable it to persist in iron- deprived microenvironments of human granulomas

AU - Kurthkoti, Krishna

AU - Amin, Hamel

AU - Marakalala, Mohlopheni J.

AU - Ghanny, Saleena

AU - Subbian, Selvakumar

AU - Sakatos, Alexandra

AU - Livny, Jonathan

AU - Fortune, Sarah M.

AU - Berney, Michael

AU - Rodriguez, G. Marcela

PY - 2017/7/1

Y1 - 2017/7/1

N2 - 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.

AB - 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.

KW - Iron acquisition

KW - Iron deprivation

KW - Iron sequestration

KW - Latent TB

KW - Mycobacterium tuberculosis

KW - Nutritional immunity

KW - Persistence

KW - TB granuloma

UR - http://www.scopus.com/inward/record.url?scp=85029148038&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029148038&partnerID=8YFLogxK

U2 - 10.1128/mBio.01092-17

DO - 10.1128/mBio.01092-17

M3 - Article

VL - 8

JO - mBio

JF - mBio

SN - 2161-2129

IS - 4

M1 - e01092-17

ER -