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）每年造成超过100万人死亡。 MTB的关键因素 成功是其抵抗免疫防御机制并建立潜在结核病感染（LTBI）的能力 免疫能力的宿主。在LTBI中，几十年来，细菌可以持续数十年 对治疗的难治性，因为抗生素通常靶向与活性生长和 增殖。 LTBI患者最初感染后的任何时候都可以患有活性结核病疾病 构成新结核病案件的巨大储层。宿主 - 细菌相互作用如何导致建立 LTBI并启用MTB在宿主中的长期存活尚不清楚。 在感染过程中，MTB必须适应宿主施加的必需微量营养素的限制。 抗菌策略被称为“营养免疫”。我们最近的工作表明， 对MTB的营养免疫力是大量的宿主铁（FE） - 序列和Fe限制因子 集中在结核性肉芽肿的中心，可能导致感染的强烈剥夺 MTB。我们还发现，在体外剥夺Fe剥夺会诱导MTB采用静止状态。 LTBI，对抗生素的耐受性，能够在没有环境FE的情况下长期存活。 此外，我们已经表明，富裕的持久性MTB有效地恢复并复制Fe 可用性提高，这使得想起了MTB感染的人的LTBI重新激活的报道 补充。基于这些观察结果，我们假设营养免疫力限制可能会触发 在感染MTB并促进LTBI的建立时，静止状态的发展。那，我们 假设阻碍MTB在FE剥夺下持续存在的能力将降低其长期保留的能力 宿主的生存能力可能构成一种在LTBI期间与MTB持久性打击的新方法。 我们最近的研究确定了锰（MN）的可用性是Fe-生存的确定因素 被剥夺的MTB。为了确定在FE饥饿下减少MTB持久性的策略，该提议试图 阐明MN持续剥夺MTB的生存能力的机制。实现目标将开放 针对病原体和/或宿主定向治疗策略的治疗研究的新途径，以针对金属 MTB持久性的要求。