The essential role of manganese in persistence of M. tuberculosis under iron starvation.

锰在铁饥饿下结核分枝杆菌持续存在中的重要作用。

• 批准号: 9894232
• 负责人: Gloria Marcela Rodriguez
• 金额: $ 25.08万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-12 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894232
• 关键词: Adopted; Antibiotics; Antioxidants; Bacillus; Binding Proteins; Cell physiology; Cessation of life; Complex; Cues; Defense Mechanisms; Development; Diagnosis; Disease; Drug resistance; Enzymes; Equilibrium; Functional disorder; Genetic Transcription; Goals; Granuloma; Growth; Heme; Hemoglobin; Homeostasis; Human; Immune; Immunocompetent; In Vitro; Infection; Ions; Iron; Knock-out; Knowledge; Leukocyte L1 Antigen Complex; Manganese; Metabolic; Metabolic Pathway; Metals; Micronutrients; Mycobacterium tuberculosis; Necrosis; Nutritional Immunity; Oxidation-Reduction; Pathway interactions; Persons; Pharmacotherapy; Physiological; Proteins; Refractory; Reporting; Role; Solubility; Starvation; Testing; Therapeutic; Therapeutic Human Experimentation; Time; Toxic effect; Treatment Efficacy; Treatment Protocols; Tuberculosis; Work; antibiotic tolerance; antimicrobial; aqueous; base; cell growth; cofactor; combat; deprivation; effective therapy; iron supplementation; latent infection; mutant; novel strategies; novel therapeutics; pathogen; pathogenic microbe; prevent; reactivation from latency; success; treatment strategy; tuberculosis treatment

Mycobacterium tuberculosis (Mtb) is responsible for over 1 million deaths each year. A key factor in Mtb success is its ability to resist immune defense mechanisms and establish latent TB infection (LTBI) in immunocompetent hosts. In LTBI, the bacilli can persist for decades in a slow-to-non-replicating state that is refractory to treatment, as antibiotics generally target cell functions associated with active growth and proliferation. Persons with LTBI can develop active TB disease at any time after the initial infection, thereby constituting an enormous reservoir of new TB cases. How the host-bacterial interplay leads to establishment of LTBI and enables prolonged survival of Mtb in the host is not clear. During infection, Mtb must adapt to essential micronutrient limitation imposed by the host as part of an antimicrobial strategy known as “nutritional immunity”. Our recent work showed that a key component of nutritional immunity against Mtb is a plethora of host iron(Fe)-sequestration and Fe-restriction factors concentrated in the center of tuberculous granulomas, likely resulting in strong Fe deprivation for the infecting Mtb. We also found that Fe deprivation in vitro induces Mtb to adopt a quiescent state reminiscent of bacilli in LTBI, tolerant to antibiotics and capable of surviving for a long time in the absence of environmental Fe. Furthermore, we have shown that Fe-starved persistent Mtb efficiently recovers and replicates when Fe availability increases, which is reminiscent of reports of reactivation of LTBI in Mtb-infected humans receiving Fe- supplementation. Based on these observations we postulate that Fe restriction by nutritional immunity may trigger the development of a quiescent state in infecting Mtb and promote the establishment of LTBI. Thus, we hypothesize that impeding Mtb ability to persist under Fe-deprivation will decrease its capacity to retain long-term viability in the host and may constitute a novel approach to combat Mtb persistence during LTBI. Our most recent studies identified availability of manganese (Mn) as a determinant factor in survival of Fe- deprived Mtb. To identify strategies to reduce Mtb persistence under Fe-starvation, this proposal seeks to elucidate the mechanisms by which Mn sustains viability of Fe-deprived Mtb. Accomplishing the aims will open new paths for therapeutic research on pathogen and/or host directed therapeutics strategies to target the metal requirements of Mtb for persistence.

结核分枝杆菌（Mtb）每年造成100多万人死亡。结核分枝杆菌的一个关键因素