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.

弓形虫病是由专性细胞内寄生虫弓形虫引起的一种机会性疾病。这 寄生虫感染了全球近20亿人。在健康个体中，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了复制性 形成（速殖子）以防止引起疾病。然而，通过转化成潜伏形式，弓形虫形成组织 大脑和心脏中的囊肿，持续一生。弓形虫组织包囊被一层厚厚的囊壁所包围 其保护寄生虫免受可用药物和宿主免疫应答的影响。缓殖子，在我们的研究中 在组织包囊中，感知环境，并能从包囊中释放出来，转化为速殖子， 导致疾病复发这经常发生在艾滋病毒/艾滋病患者中， 可能危及生命的病变在健康个体中，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， 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; 最近另一项研究证实了这一点，该研究发现， 在受感染小鼠的大脑中，导致行为改变和神经炎症。营养缺陷型 几种营养素弓形虫从宿主获得氨基酸以建立感染，从而影响宿主 细胞代谢和氨基酸利用率。我们最近证明弓形虫在体内消耗精氨酸， 感染的细胞导致宿主代谢变化，导致宿主阳离子氨基酸的更高表达 GCN 2调控的CAT 1。弓形虫感染不仅诱导CAT 1表达， 增加精氨酸转运体活性，提高受感染细胞的精氨酸水平。虽然我们取得了 精氨酸在弓形虫急性感染过程中的作用、本宿主和其他宿主的作用 慢性弓形虫病期间氨基酸的可利用性一直是令人沮丧的神秘。我们的初步研究结果 支持我们的工作假设，弓形虫调节宿主氨基酸途径，建立慢性 感染该提议将检验双宿主氨基酸代谢途径GCN 2和 mTORC 1介导脑中的寄生虫持久性。我们的实验计划包括两个独立的目标 这将阐明氨基酸代谢在弓形虫感染脑中的作用，以及氨基酸如何在弓形虫感染脑中的作用。 酸的可利用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变化。目标2将阐明 GCN 2和mTORC 1通路在弓形虫感染期间的神经改变中解决 这一观察结果的潜在机制将为深入了解寄生虫是如何导致 神经系统的改变使我们能够更好地开发新的疗法来治疗患者的弓形虫。