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

结核分枝杆菌（Mtb）每年造成超过100万人死亡。结核病的一个关键因素 成功之处在于它能够抵抗免疫防御机制，并建立潜伏性结核感染（LTBI）， 免疫活性宿主。在LTBI中，杆菌可以以缓慢至非复制状态持续数十年， 难治性，因为抗生素通常靶向与活跃生长相关的细胞功能， 增殖LTBI患者可在初次感染后的任何时间发展为活动性结核病， 构成了新结核病病例的巨大储存库。宿主-细菌的相互作用如何导致 LTBI是否能够延长Mtb在宿主中的存活时间尚不清楚。 在感染过程中，结核分枝杆菌必须适应宿主施加的必需微量营养素限制，这是结核分枝杆菌感染的一部分。 抗微生物策略称为“营养免疫”。我们最近的研究表明， 针对结核分枝杆菌的营养免疫是过多的宿主铁（Fe）螯合和铁限制因子 集中在结核性肉芽肿的中心，可能导致感染性肉芽肿的强烈铁剥夺。 Mtb.我们还发现，铁剥夺在体外诱导结核分枝杆菌采取一种静止状态，让人联想到细菌， LTBI对抗生素有耐受性，能在缺铁环境中长期存活。 此外，我们已经表明，铁饥饿持久结核病有效地恢复和复制时，铁 可用性增加，这让人想起在接受Fe-12治疗的Mtb感染者中LTBI重新激活的报道。 补充。基于这些观察，我们假设营养免疫对铁的限制可能会引发 在感染Mtb的过程中发展为静止状态并促进LTBI的建立。因此我们 假设阻碍结核分枝杆菌在缺铁条件下持续存在能力将降低其长期保留的能力， 在宿主中的生存能力，并可能构成一种新的方法，以打击结核病持久性在LTBI。 我们最近的研究确定了锰（Mn）的可用性作为铁- 被剥夺的Mtb.为了确定在Fe饥饿下降低Mtb持久性的策略，该提议寻求 阐明锰维持铁剥夺结核分枝杆菌的生存能力的机制。实现目标将打开 针对病原体和/或宿主靶向治疗策略的治疗研究的新途径 Mtb对持久性的要求。

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.