Foam cells as drug targets in tuberculosis

充满脂质的巨噬细胞（泡沫细胞）是维持慢性结核病（TB）感染的核心。泡沫细胞 为结核分枝杆菌的生存提供了有利的生态位，因为抗菌功能是 在这些细胞中普遍下调。此外，泡沫细胞诱导组织损伤和干酪化，并促进 结核病传播。事实上，结核病引起的组织损伤程度与泡沫细胞丰度密切相关 在病变中。该提案的首要假设是，阻止泡沫细胞形成将促进 巨噬细胞介导的M.肺结核感染。我们最近发现，不像胆固醇- 在动脉粥样硬化病变、结核性肺结核的泡沫细胞丰富和坏死区域发现富含酯的泡沫细胞。 肉芽肿特别富含甘油三酯。考虑到储存脂质的不同性质， 结核性泡沫细胞的脂质积聚机制与已知的发生机制有很大不同 在动脉粥样硬化形成过程中。因此，需要针对结核病的干预措施来阻止结核病中泡沫细胞的形成。感染 与M.结核病与参与甘油三酯代谢的两种细胞途径的失调有关。 稳态：第一个是促脂肪生成的，包括两种激酶，蛋白激酶B和mTOR复合物1 (Akt/mTORC 1）;第二种是抗脂肪生成的，包括AMP活化的蛋白激酶和NAD+- 依赖性脱乙酰酶，称为sirtuins（AMPK/SIRT）。我们提出了一个双目标计划，利用临床样本， 人供体和离体巨噬细胞的实验感染以及产生坏死性 肺结核病灶（C3 HeB/FeJ）。这些实验将表征：（i）抗脂肪生成的作用， 治疗对离体感染的人巨噬细胞的抗分枝杆菌功能的影响;（ii） 激活这些通路并控制临床M.结核感染;和（iii）抗脂肪生成的作用 治疗作为C3 HeB/FeJ小鼠中TB的连续治疗。本提案的总体目标是发现 在促脂肪生成和抗脂肪生成途径中的可药物靶点，长期目标是缩短 结核病治疗的持续时间和改善结核病相关的免疫病理学。这一建议预计将导致临床 针对结核病的新型宿主导向疗法的试验。更一般地说，这些研究预计将揭示 针对非动脉粥样硬化患者适应不良巨噬细胞反应的药理学干预的潜力 疾病，并激发他们的追求。

Lipid-laden macrophages (foam cells) are central to maintaining chronic tuberculosis (TB) infection. Foam cells provide a favorable niche for survival of Mycobacterium tuberculosis, because antimicrobial functions are generally down-regulated in these cells. Moreover, foam cells induce tissue damage and caseation, and facilitate TB transmission. Indeed, the extent of TB-induced tissue damage is closely correlated with foam cell abundance in lesions. The overarching hypothesis of this proposal is that blocking foam cell formation will facilitate macrophage-mediated clearance of M. tuberculosis infection. We recently discovered that, unlike the cholesteryl- ester-rich foam cells found in atherosclerotic lesions, foam-cell-rich and necrotic areas of tuberculous granulomas are particularly enriched in triglycerides. Given the different nature of the storage lipid, the underlying lipid accumulation mechanisms in tuberculous foam cells must differ substantially from those known to occur during atherogenesis. Thus, TB-specific interventions are needed to impede foam cell formation in TB. Infection with M. tuberculosis is associated with dysregulation of two cellular pathways involved in triglyceride homeostasis: the first, which is pro-lipogenic, includes two kinases, protein kinase B and mTOR complex 1 (Akt/mTORC1); the second, which is anti-lipogenic, includes AMP-activated protein kinase and the NAD+- dependent deacetylases called sirtuins (AMPK/SIRT). We propose a two-aim plan utilizing clinical samples from human donors and experimental infections of macrophages ex vivo and of a mouse strain producing necrotic tuberculous lung lesions (C3HeB/FeJ). These experiments will characterize: (i) the effect of anti-lipogenic treatments on antimycobacterial functions of human macrophages infected ex vivo; (ii) the relationship between activation of these pathways and control of clinical M. tuberculosis infection; and (iii) the role of anti-lipogenic treatments as adjunctive therapy for TB in C3HeB/FeJ mice. The overall objective of this proposal is to discover druggable targets in the pro-lipogenic and anti-lipogenic pathways, with the long-term goal of shortening the duration of TB treatment and improving TB-related immunopathology. This proposal is expected to lead to clinical trials of novel host-directed therapeutics against TB. More generally, these studies are expected to reveal the potential for pharmacological interventions targeting maladaptive macrophage responses in non-atherogenic diseases and to stimulate their pursuit.