Metabolic basis for the persistence of dormant Toxoplasma gondii infection

休眠弓形虫感染持续存在的代谢基础

• 批准号: 10562309
• 负责人: DAVID J BZIK
• 金额: $ 40.79万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-23 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10562309
• 关键词: Acceleration; Acute; Address; Affect; Agglutinins; Amylopectin; Back; Binding; Biology; Biomass; Carbon; Cell Respiration; Cells; Central Nervous System; Cessation of life; Cyst; Cytoplasmic Granules; Data; Defect; Development; Dolichos; Electron Transport; Environment; Enzymes; Exhibits; Glucans; Glucose; Glycogen Phosphorylase; HIV; Habitats; Human; Immune response; Immunosuppression; Infection; Invaded; Knowledge; Lectin; Life; Maintenance; Metabolic; Metabolism; Microbe; Mitochondria; Molecular; Muscle Fibers; Neurocognitive; Neurocognitive Deficit; Neurons; Nutrient; Nutritional; Oxidative Phosphorylation; Parasites; Persons; Pharmaceutical Preparations; Phenotype; Phosphorylation; Physiological; Polysaccharides; Production; Protein Kinase; Skeletal Muscle; Source; Starvation; Stress; Structure; Testing; Therapeutic; Thick; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Work; blood-brain barrier crossing; cell type; co-infection; enzyme activity; glycosylation; hexokinase; intracellular parasitism; microbial; monocyte; mutant; neutrophil; prevent; skeletal muscle differentiation; succinylated wheat germ agglutinin; sugar; toxoplasmic encephalitis

Dormant Toxoplasma gondii [Toxoplasma] infection is characterized by dormant bradyzoite stage parasites that reside within thick-walled cysts that develop inside neurons in the central nervous system. Cysts provide a structural and physiological habitat that sustains the viability of dormant bradyzoite stage parasites. While many targets and therapeutics have been identified to effectively treat the active Toxoplasma infection that is defined by rapidly replicating tachyzoite stage parasites, therapeutic strategies or drugs that eliminate dormant bradyzoites and their cysts have not been identified. The identification of potential targets to perturb or eliminate dormancy has proven challenging for many microbes, including Toxoplasma, because microbial dormancy is characterized by a reduced metabolic state that sustains viability but not replication. Several lines of evidence support the hypothesis that dormant bradyzoites have markedly reduced mitochondrial functions and rely more heavily on acquiring host glucose not just for energy production but also to meet an increased demand for glucose to build bradyzoite-stage amylopectin and cyst wall glycan biomass. Consistent with this hypothesis, our data has shown that blocking the utilization of host glucose markedly reduced the development as well as the persistence of dormant stage bradyzoites. Here, we propose to define the metabolic basis that underpins the ability of glucose starvation to prevent the development and persistence of dormant bradyzoites. Targeting mitochondrial functions such as the electron transport chain has been shown to have a partial ability to perturb but not to eliminate dormancy. We hypothesize that targeting glucose or glucose + lactate utilization in combination with inhibition of mitochondrial function will accelerate the demise of dormant bradyzoites and their cysts. The work in this proposal charts a way forward to identify a metabolic basis to eliminate Toxoplasma dormancy.

休眠的弓形虫[弓形虫]感染的特征是休眠的胸骨寄生虫 这位于中枢神经系统中神经元内发展的厚壁囊肿内。囊肿提供 一种结构和生理栖息地，可维持休眠的胸肌寄生虫的生存能力。尽管 已经确定了许多靶标和治疗剂可有效治疗活性毒品感染 通过快速复制tachyzoite阶段寄生虫，消除治疗策略或药物来定义 尚未确定休眠的胸肌及其囊肿。识别潜在目标 或消除休眠已被证明对包括弓形虫在内的许多微生物具有挑战性，因为微生物 休眠的特征是降低的代谢状态，可持续可行性但不复制。一些 证据线支持了休眠的胸肌明显降低线粒体的假设 功能和更大程度地依赖于获取宿主葡萄糖不仅用于能源生产，还可以实现 增加对葡萄糖的需求增加，以构建铁二核阶段的链托蛋白和囊肿壁聚糖生物质。持续的 通过这一假设，我们的数据表明，阻止宿主葡萄糖的利用显着降低了 发育以及休眠阶段的Bradyzoites的持久性。在这里，我们建议定义 代谢基础是葡萄糖饥饿阻止发展和持久性的能力 休眠的胸肌。靶向线粒体功能，例如电子传输链 证明具有部分扰动的能力，但不能消除休眠状态。我们假设靶向葡萄糖 或葡萄糖 +乳酸利用与线粒体功能的抑制结合使用将加速 休眠的Bradyzoites及其囊肿的灭亡。该提案中的工作图表了一个前进的道路来识别 消除弓形虫休眠的代谢基础。