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: 10558212
• 负责人: Leonardo da Silva Augusto
• 金额: $ 21.8万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558212
• 关键词: AIDS/HIV problem; 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; Genes; 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; base; chronic infection; cognitive change; cognitive neuroscience; flu; inhibitor; insight; nervous system disorder; neuroinflammation; novel therapeutics; obligate intracellular parasite; transcriptome

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.

弓形虫病是一种由专性细胞内寄生虫弓形虫引起的机会性疾病。这 全球已有近20亿人感染了寄生虫。在健康的人中，弓形虫感染通常是 无症状或表现为轻微的流感样症状，因为免疫系统有效地保持复制 形式(速殖子)不会引起疾病。然而，通过转化为潜伏的形式，弓形虫形成组织 脑部和心脏的囊肿会持续终生。弓形虫组织囊被厚壁包围。 它保护寄生虫对可用药物和宿主的免疫反应。慢速动物，发现的潜伏形态 在组织包囊中，感知环境，可以从包囊中释放并转化为速殖子， 这会导致疾病的重新激活。这经常发生在艾滋病毒/艾滋病患者身上，它会导致脑部 可能危及生命的损伤。在健康个体中，慢性弓形虫病与 和神经认知障碍，以及精神和神经障碍。我们之前已经证明了 神经炎症是导致弓形虫感染小鼠行为改变的主要因素之一； 最近的另一项研究证实了这一点，该研究发现，几个与氨基酸相关的基因是失调的。 在受感染的小鼠的大脑中，导致行为改变和神经炎症。营养缺乏症 几种营养素弓形虫从宿主获取氨基酸来建立感染，从而影响宿主 细胞代谢和氨基酸利用率。我们最近证明了弓形虫在体内耗尽精氨酸 感染细胞导致宿主代谢变化，导致宿主阳离子氨基酸表达增加 转运蛋白-1(CAT1)受GCN2调控。弓形虫感染不仅诱导CAT1的表达，而且 增加精氨酸转运蛋白的活性，提高感染细胞的精氨酸水平。虽然我们已经做出了 精氨酸在弓形虫急性感染中的作用及其与宿主作用的研究进展 慢性弓形虫病期间的氨基酸供应一直令人沮丧地神秘。我们的初步调查结果 支持我们的工作假设，即弓形虫调节宿主氨基酸途径以建立慢性 感染。这一提议将检验两种宿主氨基酸代谢途径GCN2和GCN2的假设 MTORC1，介导寄生虫在大脑中的持久性。我们的实验计划有两个独立的目标 这将阐明氨基酸代谢在弓形虫感染大脑中的作用以及氨基酸是如何 酸的可获得性有助于慢性感染小鼠的行为变化。目标1将决定 小鼠弓形虫组织包囊发育过程中宿主氨基酸水平的研究目标2将阐明 GCN2和mTORC1通路在弓形虫感染时神经系统改变中的作用解决问题 这一观察结果背后的机制将为寄生虫如何引起 神经系统的改变使我们处于更好的地位，可以开发治疗弓形虫的新疗法。