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

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 成功的是它有能力抵抗免疫防御机制，建立潜在的结核病感染(LTBI) 有免疫能力的宿主。在LTBI中，杆菌可以在缓慢到不复制的状态下持续数十年，即 难治性，因为抗生素通常针对与活跃的生长和 扩散。肺结核病患者可在首次感染后的任何时间患上活动性结核病，因此 构成了新结核病病例的巨大蓄水池。宿主-细菌的相互作用如何导致建立 LTBI能否使结核分枝杆菌在宿主中存活时间延长尚不清楚。 在感染期间，结核分枝杆菌必须适应宿主施加的基本微量营养素限制，作为 抗菌策略被称为“营养免疫”。我们最近的研究表明， 对结核分枝杆菌的营养免疫是宿主铁(Fe)储存和铁限制因子过多 集中在结核肉芽肿的中心，可能导致强烈的铁缺乏以供感染 山地车。我们还发现，在体外缺铁诱导结核分枝杆菌采取一种令人想起杆菌的静止状态. LTBI，对抗生素耐受，能在没有环境铁的情况下长期存活。 此外，我们还证明了铁缺乏的持久性结核分枝杆菌在铁缺乏时可以有效地恢复和复制 可获得性增加，这让人想起有报道称，结核分枝杆菌感染者在接受铁剂治疗后，LTBI重新激活。 补充。根据这些观察，我们推测营养免疫导致的铁限制可能引发 使结核分枝杆菌感染进入静止期，促进结核分枝杆菌感染的建立。因此，我们 假设阻碍结核分枝杆菌在缺铁条件下持续存在的能力将降低其长期保持的能力 在宿主中的生存能力，并可能构成一种新的方法来对抗结核分枝杆菌在LTBI期间的持久性。 我们最新的研究发现，锰(Mn)的有效性是铁存活的决定因素。 被剥夺了Mtb。为了确定在铁饥饿情况下减少结核分枝杆菌持久性的策略，该提案试图 阐明了锰维持缺铁结核分枝杆菌活力的机制。实现这些目标将开启 针对金属的病原体和/或宿主导向治疗策略的治疗研究的新途径 MTB对持久化的要求。

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.