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Abstract：
Tuberculosis (TB) is a leading cause of death among infectious diseases worldwide due to latent TB infection, which is the critical step for the successful pathogenic cycle. In this stage, Mycobacterium tuberculosis resides inside the host in a dormant and antibiotic-tolerant state. Latent TB infection can also lead to multisystemic diseases because M. tuberculosis invades virtually all organs, including ocular tissues. Ocular tuberculosis (OTB) occurs when the dormant bacilli within the ocular tissues reactivate, originally seeded by hematogenous spread from pulmonary TB. Histological evidence suggests that retinal pigment epithelium (RPE) cells play a central role in immune privilege and in protection from antibiotic effects, making them an anatomical niche for invading M. tuberculosis. RPE cells exhibit high tolerance to environmental redox stresses, allowing phagocytosed M. tuberculosis bacilli to maintain viability in a dormant state. However, the microbiological and metabolic mechanisms determining the interaction between the RPE intracellular environment and phagocytosed M. tuberculosis are largely unknown. Here, liquid chromatography-mass spectrometry metabolomics were used to illuminate the metabolic state within RPE cells reprogrammed to harbor dormant M. tuberculosis bacilli and enhance antibiotic tolerance. Timely and accurate diagnosis as well as efficient chemotherapies are crucial in preventing the poor visual outcomes of OTB patients. Unfortunately, the efficacy of current methods is highly limited. Thus, the results will lead to propose a novel therapeutic option to synthetically kill the dormant M. tuberculosis inside the RPE cells by modulating the phenotypic state of M. tuberculosis and laying the foundation for a new, innovative regimen for treating OTB.
OBJECTIVE: Understanding the metabolic environment within the retinal pigment epithelium (RPE) cells altered by infection with Mycobacterium tuberculosis and mycobacterial dormancy is crucial to identify new therapeutic methods to cure ocular tuberculosis. The present study showed that RPE cellular metabolism is altered to foster intracellular M. tuberculosis to enter into the dormant and drug-tolerant state, thereby blunting the efficacy of anti-tuberculosis chemotherapy. RPE cells serve as an anatomical niche as the cells protect invading bacilli from antibiotic treatment. LC-MS metabolomics of RPE cells after co-treatment with H2O2 and M. tuberculosis infection showed that the intracellular environment within RPE cells is enriched with a greater level of oxidative stress. The antibiotic tolerance of intracellular M. tuberculosis within RPE cells can be restored by a metabolic manipulation strategy such as co-treatment of antibiotic with the most downstream glycolysis metabolite, phosphoenolpyruvate.
OBJECTIVE: Understanding the metabolic environment within the retinal pigment epithelium (RPE) cells altered by infection with Mycobacterium tuberculosis and mycobacterial dormancy is crucial to identify new therapeutic methods to cure ocular tuberculosis. The present study showed that RPE cellular metabolism is altered to foster intracellular M. tuberculosis to enter into the dormant and drug-tolerant state, thereby blunting the efficacy of anti-tuberculosis chemotherapy. RPE cells serve as an anatomical niche as the cells protect invading bacilli from antibiotic treatment. LC-MS metabolomics of RPE cells after co-treatment with H2O2 and M. tuberculosis infection showed that the intracellular environment within RPE cells is enriched with a greater level of oxidative stress. The antibiotic tolerance of intracellular M. tuberculosis within RPE cells can be restored by a metabolic manipulation strategy such as co-treatment of antibiotic with the most downstream glycolysis metabolite, phosphoenolpyruvate.
摘要：
结核病（TB）是世界范围内由于潜伏性TB感染而导致的传染病死亡的主要原因。这是成功的致病周期的关键步骤。在这个阶段,结核分枝杆菌以休眠状态和耐抗生素状态驻留在宿主内部。潜伏结核感染也可导致多系统疾病，因为结核分枝杆菌侵入几乎所有器官，包括眼组织。眼结核（OTB）发生在眼组织内的休眠杆菌重新激活时，最初是由肺结核病的血源性传播播种的。组织学证据表明，视网膜色素上皮（RPE）细胞在免疫特权和保护抗生素作用中起着核心作用。使它们成为入侵结核分枝杆菌的解剖学利基。RPE细胞表现出对环境氧化还原应力的高耐受性，允许吞噬的结核分枝杆菌在休眠状态下保持活力。然而,决定RPE细胞内环境与吞噬的结核分枝杆菌之间相互作用的微生物和代谢机制在很大程度上是未知的。这里,使用液相色谱-质谱代谢组学来阐明RPE细胞内的代谢状态，该细胞重编程为具有休眠结核分枝杆菌并增强抗生素耐受性。及时准确的诊断以及有效的化学疗法对于预防OTB患者的不良视力至关重要。不幸的是,目前方法的功效是非常有限的。因此，结果将导致提出一种新的治疗选择，通过调节结核分枝杆菌的表型状态来合成杀死RPE细胞内休眠的结核分枝杆菌，并为新的，治疗OTB的创新方案。
目的：了解结核分枝杆菌感染和分枝杆菌休眠改变的视网膜色素上皮（RPE）细胞内的代谢环境对于确定治疗眼结核的新治疗方法至关重要。本研究表明，RPE细胞代谢发生改变，促进细胞内结核分枝杆菌进入休眠状态和耐药状态，从而削弱了抗结核化疗的疗效。RPE细胞充当解剖生态位,因为细胞保护入侵杆菌免受抗生素治疗。用H2O2和结核分枝杆菌感染共同处理后的RPE细胞的LC-MS代谢组学表明，RPE细胞内的细胞内环境富含更高水平的氧化应激。RPE细胞内胞内结核分枝杆菌的抗生素耐受性可以通过代谢操作策略来恢复，例如抗生素与最下游的糖酵解代谢物共同治疗，磷酸烯醇丙酮酸。
目的：了解结核分枝杆菌感染和分枝杆菌休眠改变的视网膜色素上皮（RPE）细胞内的代谢环境对于确定治疗眼结核的新治疗方法至关重要。本研究表明，RPE细胞代谢发生改变，促进细胞内结核分枝杆菌进入休眠状态和耐药状态，从而削弱了抗结核化疗的疗效。RPE细胞充当解剖生态位,因为细胞保护入侵杆菌免受抗生素治疗。用H2O2和结核分枝杆菌感染共同处理后的RPE细胞的LC-MS代谢组学表明，RPE细胞内的细胞内环境富含更高水平的氧化应激。RPE细胞内胞内结核分枝杆菌的抗生素耐受性可以通过代谢操作策略来恢复，例如抗生素与最下游的糖酵解代谢物共同治疗，磷酸烯醇丙酮酸。
