Origins of zinc starvation in Mycobacterium tuberculosis during chronic infection

结核分枝杆菌慢性感染期间锌饥饿的起源

• 批准号: 10286274
• 负责人: Anil Kumar Ojha
• 金额: $ 22.37万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-08 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10286274
• 关键词: Aminoglycoside resistance; Aminoglycosides; Antibiotic Therapy; Antibiotics; Bacterial Infections; Binding; Biological Availability; Calcium Binding; Cells; Chronic; Disease; Dose; Drug resistance; Drug resistance in tuberculosis; Environment; Frequencies; Growth; Hibernation; Host Defense; Hypoxia; Immune system; Immunologist; Infection; Ions; Knowledge; Lesion; Leukocyte L1 Antigen Complex; Lung; Mediating; Metals; Multidrug-Resistant Tuberculosis; Mus; Mycobacterium smegmatis; Mycobacterium tuberculosis; Neutrophil Infiltration; Neutrophilic Infiltrate; Nutrient; Nutrient Depletion; Nutritional Immunity; Oral; Oral Administration; Pathogenesis; Phagosomes; Pharmaceutical Preparations; Phenotype; Population; Proteins; Public Health; Recombinants; Regimen; Reporter; Resistance; Ribosomal Interaction; Ribosomal RNA; Ribosomes; Role; S100 Proteins; S100A8 gene; S100A9 gene; Site; Starvation; Streptomycin; Testing; Therapeutic; Transition Elements; Treatment Efficacy; Treatment Protocols; Treatment outcome; Tuberculosis; Y protein; Zinc; Zinc Oxide; Zinc supplementation; aerosolized; base; chronic infection; direct application; extracellular; improved; insight; mycobacterial; nanoparticle; neutrophil; novel strategies; pathogen; response; tuberculosis chemotherapy; tuberculosis treatment

Summary Tuberculosis (TB) is a major public health burden in the world: over a million people die of the disease every year and an estimated one third of the world’s population harbor the pathogen Mycobacterium tuberculosis (Mtb). Treatment of TB requires 6 to 9 months of an antibiotic regimen comprising of multiple antibiotics. Difficulties in treatment of TB are largely attributed to non-inheritable drug resistance in the pathogen that are considered to be developed due to unique microenvironments in the host (e.g. nutrient depletion, hypoxia and antibiotic exposure). Recently, we uncovered one such condition: zinc starvation. In response to zinc starvation both Mycobacterium smegmatis and Mycobacterium tuberculosis induce ribosome remodeling and ribosome hibernation. Ribosome remodeling involves replacement of multiple ribosomal (r-) proteins containing the zinc-binding CXXC motif (therefore called C+ r-proteins) by their motif- free C- paralogues. Ribosome hibernation involves binding of mycobacterial protein Y (Mpy) to the decoding center of the C- ribosome. Ribosome remodeling occurs at a zinc concentration that permits growth, whereas ribosome hibernation occurs at a growth-restrictive concentration of zinc. Moreover, mycobacterial cells harboring remodeled and hibernating ribosomes are resistant to aminoglycosides and spectinamides. Furthermore, we demonstrated that zinc in the host lung environment during chronic Mtb infection is low enough to induce ribosome remodeling and Mpy- dependent resistance to streptomycin, an aminoglycoside used in the treatment of multi-drug resistant TB. However, the underlying cause for zinc starvation in Mtb during chronic infection is not known. Based on the idea that metal ion starvation during bacterial infections is an innate host defense strategy, called nutritional immunity, we propose to identify the components of host immune system responsible for zinc starvation in Mtb (Aim 1), and determine the potential of zinc oxide nanoparticles as an adjunct therapeutic (Aim 2). Upon completion of the project we will gain further insight into the cause of zinc starvation and related ribosome remodeling/hibernation in Mtb during chronic infection, and develop a therapeutic strategy to minimize the drug resistance caused by these changes to the ribosome in Mtb.

概括 结核病（TB）是世界上主要的公共卫生负担：超过一百万人死于结核病 每年都会发生这种疾病，估计世界上三分之一的人口携带这种病原体 结核分枝杆菌 (Mtb)。结核病的治疗需要 6 至 9 个月的抗生素治疗 包含多种抗生素的治疗方案。结核病治疗的困难主要归因于 病原体中的非遗传​​性耐药性被认为是由于独特的原因而产生的 宿主的微环境（例如营养耗尽、缺氧和抗生素暴露）。最近， 我们发现了这样一种情况：缺锌。为了应对锌缺乏， 耻垢分枝杆菌和结核分枝杆菌诱导核糖体重塑并 核糖体冬眠。核糖体重塑涉及多个核糖体 (r-) 的替换 含有锌结合 CXXC 基序的蛋白质（因此称为 C+ r 蛋白） 免费的C-旁系同源物。核糖体冬眠涉及分枝杆菌蛋白 Y (Mpy) 与 C-核糖体的解码中心。核糖体重塑发生在锌浓度为 允许生长，而核糖体冬眠发生在锌的生长限制浓度下。 此外，含有重塑和冬眠核糖体的分枝杆菌细胞对 氨基糖苷类和奇酰胺类。此外，我们证明宿主肺中的锌 慢性 Mtb 感染期间的环境足够低，足以诱导核糖体重塑和 Mpy- 对链霉素的依赖性耐药性，链霉素是一种用于治疗多药治疗的氨基糖苷类药物 耐药结核病。然而，慢性感染期间结核分枝杆菌缺锌的根本原因是 不知道。基于细菌感染期间金属离子饥饿是先天宿主的观点 防御策略，称为营养免疫，我们建议识别宿主的成分 免疫系统导致结核分枝杆菌锌缺乏（目标 1），并确定锌的潜力 氧化物纳米颗粒作为辅助治疗剂（目标 2）。项目完成后我们将获得 进一步深入了解锌饥饿和相关核糖体重塑/冬眠的原因 慢性感染期间的结核分枝杆菌，并制定治疗策略以尽量减少耐药性 由结核分枝杆菌核糖体的这些变化引起。