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We present evidence of iron restriction in human necrotic granulomas and demonstrate that under iron starvation\n            <jats:italic>M. tuberculosis<\/jats:italic>\n            persists, refractive to antibiotics and capable of restarting replication when iron is made available. Transcriptomics and metabolomic analyses indicated that the persistence of\n            <jats:italic>M. tuberculosis<\/jats:italic>\n            under iron starvation is dependent on strict control of endogenous Fe utilization and is associated with upregulation of pathogenicity and intrinsic antibiotic resistance determinants.\n            <jats:italic>M. tuberculosis<\/jats:italic>\n            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.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            One-third of the world population may harbor persistent\n            <jats:italic>M. tuberculosis<\/jats:italic>\n            , 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\n            <jats:italic>M. tuberculosis<\/jats:italic>\n            persistence in infected individuals. Iron is an essential nutrient for\n            <jats:italic>M. tuberculosis<\/jats:italic>\n            growth. In this study, we show, first, that in human granulomas the immune defense creates microenvironments in which\n            <jats:italic>M. tuberculosis<\/jats:italic>\n            likely experiences drastic Fe deprivation and, second, that Fe-starved\n            <jats:italic>M. tuberculosis<\/jats:italic>\n            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\n            <jats:italic>M. tuberculosis<\/jats:italic>\n            and promote chronic TB. We also identified vulnerabilities of iron-restricted persistent\n            <jats:italic>M. tuberculosis<\/jats:italic>\n            , which can be exploited for the design of new antitubercular therapies.\n          <\/jats:p>","DOI":"10.1128\/mbio.01092-17","type":"journal-article","created":{"date-parts":[[2017,8,16]],"date-time":"2017-08-16T00:10:15Z","timestamp":1502842215000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":127,"title":["The Capacity of\n            <i>Mycobacterium tuberculosis<\/i>\n            To Survive Iron Starvation Might Enable It To Persist in Iron-Deprived Microenvironments of Human Granulomas"],"prefix":"10.1128","volume":"8","author":[{"given":"Krishna","family":"Kurthkoti","sequence":"first","affiliation":[{"name":"Public Health Research Institute at New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamel","family":"Amin","sequence":"additional","affiliation":[{"name":"Public Health Research Institute at New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohlopheni J.","family":"Marakalala","sequence":"additional","affiliation":[{"name":"Department of Immunology and Infectious Diseases, Harvard T. 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