Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States.
Division of Cardiothoracic Surgery, University of Alabama at Birmingham, Birmingham, AL, United States.
Front Immunol. 2018 May 3;9:860. doi: 10.3389/fimmu.2018.00860. eCollection 2018.
Iron is an essential factor for the growth and virulence of (. However, little is known about the mechanisms by which the host controls iron availability during infection. Since ferritin heavy chain (FtH) is a major intracellular source of reserve iron in the host, we hypothesized that the lack of FtH would cause dysregulated iron homeostasis to exacerbate TB disease. Therefore, we used knockout mice lacking FtH in myeloid-derived cell populations to study disease progression. We found that FtH plays a critical role in protecting mice against , as evidenced by increased organ burden, extrapulmonary dissemination, and decreased survival in mice. Flow cytometry analysis showed that reduced levels of FtH contribute to an excessive inflammatory response to exacerbate disease. Extracellular flux analysis showed that FtH is essential for maintaining bioenergetic homeostasis through oxidative phosphorylation. In support of these findings, RNAseq and mass spectrometry analyses demonstrated an essential role for FtH in mitochondrial function and maintenance of central intermediary metabolism . Further, we show that FtH deficiency leads to iron dysregulation through the hepcidin-ferroportin axis during infection. To assess the clinical significance of our animal studies, we performed a clinicopathological analysis of iron distribution within human TB lung tissue and showed that severely disrupts iron homeostasis in distinct microanatomic locations of the human lung. We identified hemorrhage as a major source of metabolically inert iron deposition. Importantly, we observed increased iron levels in human TB lung tissue compared to healthy tissue. Overall, these findings advance our understanding of the link between iron-dependent energy metabolism and immunity and provide new insight into iron distribution within the spectrum of human pulmonary TB. These metabolic mechanisms could serve as the foundation for novel host-directed strategies.
铁是生长和毒力的必需因素。然而，宿主在感染过程中如何控制铁的可用性的机制知之甚少。由于铁蛋白重链（FtH）是宿主中储备铁的主要细胞内来源，我们假设缺乏 FtH 会导致铁稳态失调，从而加重结核病。因此，我们使用缺乏髓样细胞群体中 FtH 的敲除小鼠来研究疾病进展。我们发现 FtH 在保护小鼠免受侵害方面起着关键作用，这表现在器官负担增加、肺外传播和感染小鼠的存活率降低。流式细胞术分析表明，FtH 水平降低导致炎症反应过度，从而加重疾病。细胞外通量分析表明，FtH 对于通过氧化磷酸化维持生物能量稳态是必不可少的。为了支持这些发现，RNAseq 和质谱分析表明 FtH 在维持线粒体功能和中间代谢物的中央代谢中起关键作用。此外，我们表明 FtH 缺乏会通过感染期间的铁调素-亚铁蛋白轴导致铁失调。为了评估我们的动物研究的临床意义，我们对人类结核病肺组织中的铁分布进行了临床病理分析，结果表明严重破坏了人类肺部不同微解剖位置的铁稳态。我们确定出血是代谢惰性铁沉积的主要来源。重要的是，我们观察到与健康组织相比，人类结核病肺组织中的铁水平增加。总的来说，这些发现增进了我们对铁依赖性能量代谢与免疫之间联系的理解，并为人类肺结核范围内的铁分布提供了新的见解。这些代谢机制可以作为新的宿主定向策略的基础。
