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.

弓形虫感染的特征是休眠的缓殖子期寄生虫 存在于中枢神经系统神经元内部发育的厚壁囊肿中。囊肿提供 维持休眠的缓殖子阶段寄生虫生存能力的结构和生理学栖息地。而 已经鉴定了许多靶点和治疗剂来有效治疗活动性弓形虫感染， 定义为快速复制的速殖子阶段寄生虫，治疗策略或药物， 休眠的缓殖子和它们的包囊还没有被鉴定出来。识别潜在的干扰目标 或消除休眠已被证明对许多微生物具有挑战性，包括弓形虫，因为微生物 休眠的特征在于维持生存力但不维持复制的降低的代谢状态。几 一系列的证据支持这一假设，即休眠的缓殖子显著减少了线粒体 功能和更严重地依赖于获取宿主葡萄糖，不仅用于能量生产，还用于满足 增加对葡萄糖的需求以构建缓殖子阶段支链淀粉和囊壁聚糖生物量。一致 根据这一假设，我们的数据表明，阻断宿主葡萄糖的利用， 发育以及休眠期缓殖子的持续存在。在这里，我们建议定义 代谢基础，支持葡萄糖饥饿的能力，以防止发展和持久性 休眠的缓殖子针对线粒体功能，如电子传递链， 显示具有部分扰乱但不能消除休眠的能力。我们假设以葡萄糖为目标 或葡萄糖+乳酸盐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。本提案中的工作指明了一条前进的道路， 消除弓形虫休眠的代谢基础。