The Capacity of Mycobacterium tuberculosis To Survive Iron Starvation Might Enable It To Persist in Iron-Deprived Microenvironments of Human Granulomas

Kurthkoti, Krishna and Amin, Hamel and Marakalala, Mohlopheni J and Ghanny, Saleena and Subbian, Selvakumar and Sakatos, Alexandra and Livny, Jonathan and Fortune, Sarah M and Berney, Michael and Rodriguez, G Marcela (2017) The Capacity of Mycobacterium tuberculosis To Survive Iron Starvation Might Enable It To Persist in Iron-Deprived Microenvironments of Human Granulomas. In: MBIO, 8 (4).

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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.

Item Type:	Journal Article
Publication:	MBIO
Additional Information:	Copy right for this article belongs to the AMER SOC MICROBIOLOGY, 1752 N ST NW, WASHINGTON, DC 20036-2904 USA
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited:	23 Sep 2017 05:02
Last Modified:	03 Oct 2018 15:05
URI:	http://eprints.iisc.ac.in/id/eprint/57879

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