The role of host amino acid metabolism in behavioral changes during latent toxoplasmosis

宿主氨基酸代谢在潜伏性弓形体病行为变化中的作用

• 批准号: 10597992
• 负责人: Leonardo da Silva Augusto
• 金额: $ 19.75万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597992
• 关键词: Affect; Aging; Amino Acid Metabolism Pathway; Amino Acids; Arginine; Basic Amino Acid Transport Systems; Behavior; Behavioral; Brain; Cells; Cellular Metabolic Process; Cerebral cortex; Chronic; Cyst; Cytosol; Data; Development; Disease; Environment; Frustration; Genes; HIV/AIDS; Heart; Immune response; Immune system; Individual; Infection; Knock-out; Lesion; Life; Lysosomes; Magnetic Resonance Imaging; Measures; Mediating; Mental disorders; Metabolic; Mus; Nerve Degeneration; Neurocognitive Deficit; Neurologic; Nutrient; Parasites; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Positioning Attribute; Publishing; Role; Stains; Supplementation; Symptoms; Techniques; Testing; Thick; Tissues; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; acute infection; amino acid metabolism; chronic infection; cognitive change; cognitive neuroscience; flu; inhibitor; insight; nervous system disorder; neuroinflammation; novel therapeutics; obligate intracellular parasite; transcriptomic profiling

Toxoplasmosis is an opportunistic disease caused by the obligate intracellular parasite Toxoplasma gondii. This parasite has been infected nearly 2 billion people globally. In healthy individuals, Toxoplasma infection is usually asymptomatic or it presents as mild flu-like symptoms, as the immune system effectively keeps the replicative forms (tachyzoites) from causing illness. However, by converting into latent forms, Toxoplasma forms tissue cysts in the brain and heart that persist for a lifetime. Toxoplasma tissue cysts are surrounded by a thick wall which protects the parasites to available drugs and host immune response. Bradyzoites, the latent forms found in tissue cysts, sense the environment and can be released from the cysts and transformed into tachyzoites, which results in reactivation of the disease. This frequently occurs in HIV/AIDS patients, and it causes brain lesions that can be life-threatening. In healthy individuals, there is a correlation between chronic toxoplasmosis and neurocognitive impairment, as well as mental and neurological disorders. We previously demonstrated that neuroinflammation is one of the major factors that contribute to behavioral changes in Toxoplasma-infected mice; this was recently confirmed by another study that found that several amino acid related genes are dysregulated in the brains of infected mice, contributing to behavioral alterations and neuroinflammation. Auxotrophic for several nutrients Toxoplasma acquires amino acids from the host to establish infection, which affects the host cell metabolism and amino acid availability. We recently demonstrated that Toxoplasma depletes arginine in infected cells leading to host metabolic changes resulting in higher expression of host cationic amino acid transporter-1 (CAT1) regulated by GCN2. Toxoplasma infection induces not only CAT1 expression but also increases the arginine transporter activity, elevating the arginine levels of infected cells. While we have made progress in understanding the role of arginine during Toxoplasma acute infection, the role of this and other host amino acid availability during chronic toxoplasmosis has been frustratingly mysterious. Our preliminary findings support our working hypothesis that Toxoplasma modulates host amino acid pathways to establish chronic infection. This proposal will test the hypothesis that two-host amino acid metabolism pathways, GCN2 and mTORC1, mediate parasite persistence in the brain. Our experimental plan consists of two independent aims that will elucidate the role of amino acid metabolism during Toxoplasma infection in the brain and how amino acid availability contribute to behavioral changes in chronically infected mice. Aim 1 will determine the role of host amino acid levels during development of Toxoplasma tissue cysts in mice. Aim 2 will elucidate the role of GCN2 and mTORC1 pathways in neurological alterations during Toxoplasma infection. Resolving the mechanism underlying this observation will provide much needed insight into how the parasite causes neurological alterations putting us in a better position to develop novel therapies to treat Toxoplasma in patients.

弓形虫病是由强制性细胞内寄生虫弓形虫引起的机会性疾病。这 寄生虫已被全球感染了近20亿人。在健康的个体中，弓形虫感染通常是 无症状或它作为轻度流感样症状表现出来，因为免疫系统有效地保持复制性 引起疾病的形式（tachyzoites）。但是，通过转化为潜在形式，弓形虫形成组织 一生中持续存在的大脑和心脏囊肿。弓形虫组织囊肿被厚壁包围 保护寄生虫可用的药物和宿主免疫反应。 Bradyzoites，发现的潜在形式 在组织囊肿中，感知环境，可以从囊肿中释放出来，并转化为tachyzoites， 这导致疾病重新激活。这经常发生在艾滋病毒/艾滋病患者中，并引起大脑 可能威胁生命的病变。在健康的个体中，慢性毒性质症之间存在相关性 以及神经认知障碍以及心理和神经系统疾病。我们以前证明了 神经炎症是导致弓形虫感染小鼠行为变化的主要因素之一。 最近的另一项研究发现了这一点，发现几个相关的基因失调 在被感染的小鼠的大脑中，导致行为改变和神经炎症。可营养的 几种营养物质毒品可从宿主那里获取氨基酸以建立感染，这会影响宿主 细胞代谢和氨基酸的可用性。我们最近证明了毒素耗尽精氨酸 感染的细胞导致宿主代谢变化，导致宿主阳离子氨基酸的较高表达 由GCN2调节的转运蛋白1（CAT1）。弓形虫感染不仅引起CAT1表达，还会引起 增加精氨酸转运蛋白活性，升高感染细胞的精氨酸水平。当我们做 理解精氨酸在弓形虫急性感染中的作用的进展，该宿主和其他宿主的作用 慢性弓形虫病期间的氨基酸可用性令人沮丧。我们的初步发现 支持我们的工作假设，即毒品毒素调节宿主氨基酸途径以建立慢性 感染。该提议将检验以下假设：两个宿主氨基酸代谢途径，GCN2和 MTORC1，介导大脑中的寄生虫持久性。我们的实验计划包括两个独立目标 这将阐明在大脑中弓形虫感染中氨基酸代谢的作用以及氨基的作用 酸的可用性导致了长期感染小鼠的行为变化。 AIM 1将决定 在小鼠弓形虫组织囊肿的发展过程中，宿主氨基酸水平。 AIM 2将阐明 弓形虫感染过程中神经系统改变的GCN2和MTORC1途径。解决 该观察基础的机制将提供急需的洞察力，以了解寄生虫的原因 神经系统改变使我们处于更好的位置，可以开发出新的疗法来治疗患者的毒质量。