The Capacity of Mycobacterium tuberculosis To Survive Iron Starvation Might Enable It To Persist in Iron-Deprived Microenvironments of Human Granulomas.
The Capacity of Mycobacterium tuberculosis To Survive Iron Starvation Might Enable It To Persist in Iron-Deprived Microenvironments of Human Granulomas.
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DOI：
10.1128/mbio.01092-17
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发表时间：
2017-08-15
期刊：
影响因子：
6.4
通讯作者：
Rodriguez GM
中科院分区：
文献类型：
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作者：
Kurthkoti K;Amin H;Marakalala MJ;Ghanny S;Subbian S;Sakatos A;Livny J;Fortune SM;Berney M;Rodriguez GM
本研究旨在探讨缺铁在结核分枝杆菌持续存在中的作用。我们提出了人类坏死性肉芽肿中铁限制的证据，并证明在铁饥饿的情况下，结核分枝杆菌持续存在，对抗生素产生折射，并能够在铁可用时重新启动复制。转录学和代谢组学分析表明，结核分枝杆菌在铁饥饿条件下的持久性依赖于对内源性铁利用的严格控制，并与致病性和内在抗生素耐药决定因素的上调有关。确定了在铁饥饿中存活能力受损的结核分枝杆菌突变体。这项研究的发现促进了对可能支持人类结核病(TB)慢性化的生理环境的理解，并与有效的抗结核疗法的设计相关。世界上三分之一的人口可能患有持续的结核分枝杆菌，导致一种难以治疗的无症状感染，并可能重新激活，成为潜在的致命结核病。然而，关于引发和维持结核分枝杆菌在感染者中持续存在的因素，人们知之甚少。铁是结核分枝杆菌生长所必需的营养物质。在这项研究中，我们表明，首先，在人类肉芽肿中，免疫防御创造了微环境，在这种微环境中，结核分枝杆菌可能经历严重的铁缺乏，第二，铁饥饿的结核分枝杆菌能够在没有生长的情况下长期存活。综上所述，这些观察表明，肺中缺铁可能会引发结核分枝杆菌的持续状态，并促进慢性结核病。我们还发现了铁限制的持久性结核分枝杆菌的脆弱性，这可以被用来设计新的抗结核疗法。
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. 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.