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.

休眠弓形虫 [弓形虫] 感染的特点是休眠缓殖子阶段寄生虫 存在于中枢神经系统神经元内部发育的厚壁囊肿内。囊肿提供 维持休眠缓殖子阶段寄生虫生存能力的结构和生理栖息地。尽管 已确定许多靶点和治疗方法可以有效治疗活动性弓形虫感染 由快速复制的速殖子阶段寄生虫、治疗策略或消除药物来定义 尚未鉴定出休眠的缓殖子及其包囊。识别潜在的干扰目标 事实证明，消除休眠或消除休眠对于包括弓形虫在内的许多微生物来说具有挑战性，因为微生物 休眠的特点是代谢状态降低，维持活力但不维持复制。一些 一系列证据支持这样的假设：休眠的缓殖子显着减少了线粒体 功能并更加依赖获取宿主葡萄糖，不仅用于能量生产，而且还满足 对葡萄糖的需求增加，以构建缓殖阶段支链淀粉和囊壁聚糖生物量。持续的 根据这一假设，我们的数据表明，阻止宿主葡萄糖的利用显着降低了 发育以及休眠阶段缓殖子的持续存在。在这里，我们建议定义 支持葡萄糖饥饿防止发展和持续的代谢基础 休眠的缓殖子。针对线粒体功能（例如电子传递链）的研究已被证实 显示出具有部分扰乱休眠的能力，但不能消除休眠。我们假设以葡萄糖为目标 或葡萄糖+乳酸的利用与线粒体功能的抑制相结合将加速 休眠的缓殖子及其包囊的死亡。本提案中的工作描绘了一条前进的道路，以确定 消除弓形虫休眠的代谢基础。