The role of kynurenine pathway activation in Toxoplasma-linked schizophrenia

犬尿氨酸途径激活在弓形虫相关精神分裂症中的作用

• 批准号: 8732168
• 负责人: Erica J Duncan
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732168
• 关键词: Acoustics; Amino Acids; Antibodies; Behavior; Behavioral; Biological Assay; Biological Markers; Brain; Cells; Cerebrospinal Fluid; Chronic; Clinical; Cognitive; Cognitive deficits; Complex; Cyst; Data; Development; Diagnosis; Disease; Environmental Risk Factor; Enzymes; Felis catus; Fright; Functional disorder; General Population; Genetic; Glutamate Receptor; Human; Human Papillomavirus; Immune; Immune response; Immune system; Immunoglobulin G; Impaired cognition; Impairment; Infection; Interferon Type II; Kynurenic Acid; Kynurenine; Lead; Life; Link; Literature; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Measures; Mediating; Meta-Analysis; Metabolism; N-Methylaspartate; Neuroglia; Neurologic; Neurotransmitter Receptor; Parasites; Pathogenesis; Pathway interactions; Patients; Persons; Plasma; Play; Prevention; Process; Risk; Rodent; Role; Sampling; Schizophrenia; Series; Symptoms; TNFRSF5 gene; Testing; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Tryptophan; alpha-bungarotoxin receptor; cognitive function; cohort; cytokine; indexing; infected vector rodent; neurochemistry; novel; prevent; processing speed; public health relevance; relating to nervous system; response

DESCRIPTION (provided by applicant): Schizophrenia (SCZ) is thought to arise from the cumulative interacting effects of genetic and environmental factors. Evidence for infection with the intracellular parasite Toxoplasma gondii (TOXO) in the pathogenesis of SCZ has accumulated over several decades. Two recent meta-analyses found a highly significant elevation in the rate of chronic TOXO infection in SCZ. Humans and rodents are intermediate hosts for TOXO, which evolved a complex lifecycle and unique mechanisms to evade destruction by the host, alter host behavior, and continue its existence. TOXO is neuroinvasive, and the majority of people infected are expected to harbor T. gondii cysts in their brains for life but the parasite does not typically cause overt neurological symptoms in persons with normal immune systems. TOXO is kept in check by an ongoing immune response in which the cytokine interferon gamma (IFN¿) plays a critical role. IFN¿ is produced by several immune cells as well as brain glial cells and prevents TOXO replication by depletion of the amino acid tryptophan (Trp) that TOXO must derive from the host. IFN¿ achieves local Trp depletion by shunting Trp degradation along the kynurenine (KYN) pathway through an enzyme-controlled series of steps into KYN and kynurenic acid (KYNA). KYNA in turn is an antagonist at two neurotransmitter receptors that are believed to play a key role in SCZ: the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor and the alpha7 nicotinic acetylcholine (a7nACh) receptor. Thus there is a plausible mechanism by which TOXO could cause neurochemical abnormalities leading to SCZ, but the preferential activation of the KYN pathway has not yet been demonstrated in SCZ patients with known TOXO infection. Furthermore, a growing literature indicates that there are elevated levels of KYNA in the brains of SCZ patients, although the TOXO status of these patients has not been investigated. TOXO evolved to induce subtle behavioral dysfunction causing infected rodents to have reduced fear of cats and psychomotor slowing. In SCZ patients who are TOXO positive our pilot data indicate slowing of neural processing as indexed by prolongation of latency of the acoustic startle response, and impairment on cognitive testing. This project will investigate the hypothesis that chronic TOXO infection in SCZ leads to immune mediated activation of the KYN pathway, and that this pathway activation is associated with slowing of neural processing and cognitive deficits seen in TOXO positive SCZ. To achieve the following Aims we will assess SCZ patients and healthy controls in our VA cohort for TOXO immunoglobulin G antibody (IgG) antibody titers and plasma levels of kynurenine metabolites and IFN¿. We will examine the relationship of these neuroimmune biomarkers and acoustic startle responses, P50 gating, and cognitive function test scores by comparing four groups of 38 subjects per group): 1) TOXO-positive SCZ, 2) TOXO-negative SCZ, 3) TOXO-positive controls, 4) TOXO-negative controls. We also propose new preliminary analyses of KYN pathways in plasma and CSF. Spec Aim 1: Measure activation of the KYN pathway in SCZ subjects who are TOXO seropositive compared to TOXO-negative SCZ and control (CON) subjects with and without TOXO. Activation of this pathway will be tested by assays of KYN, KYNA, tryptophan (Trp), and the cytokine IFN¿, which induces KYN metabolism. Exploratory Aim 1a: Examine the correlation between plasma and cerebrospinal fluid (CSF) levels of KYN pathway measures in paired historical samples. We hypothesize that plasma and CSF measures will be significantly correlated. Spec Aim 2: Test the effect of TOXO infection on neural processing speed as indexed by acoustic startle latency, on impaired P50 gating, and on cognitive function in SCZ compared to CON subjects. Exploratory Aim 3: Examine whether slowing of startle latency, impaired P50 gating, and impaired cognition is predicted by KYN pathway activation, and whether it interacts with TOXO status.

描述（由申请人提供）：精神分裂症（SCZ）被认为是由遗传和环境因素的累积相互作用效应引起的。几十年来，细胞内寄生虫弓形虫 (TOXO) 感染在 SCZ 发病机制中的证据已经积累了数十年。最近的两项荟萃分析发现 SCZ 慢性 TOXO 感染率显着升高。人类和啮齿动物是 TOXO 的中间宿主，它进化出了复杂的生命周期和独特的机制来逃避宿主的破坏、改变宿主的行为并继续其存在。 TOXO 具有神经侵袭性，预计大多数感染者的大脑中会终生携带弓形虫包囊，但这种寄生虫通常不会对免​​疫系统正常的人造成明显的神经系统症状。 TOXO 受到持续免疫反应的控制，其中细胞因子干扰素γ (IFN¿) 发挥着关键作用。 IFNτ由多种免疫细胞以及脑神经胶质细胞产生，并通过消耗TOXO必须从宿主获得的氨基酸色氨酸(Trp)来阻止TOXO复制。 IFN¿通过酶控制的一系列步骤将色氨酸沿着犬尿氨酸 (KYN) 途径分流为 KYN 和犬尿酸 (KYNA)，从而实现局部色氨酸消耗。 KYNA 又是两种神经递质受体的拮抗剂，这两种受体被认为在 SCZ 中发挥关键作用：谷氨酸受体的 N-甲基-D-天冬氨酸 (NMDA) 亚型和 α7 烟碱乙酰胆碱 (a7nACh) 受体。因此，TOXO 可能通过一种可能的机制引起神经化学异常，从而导致 SCZ，但 KYN 通路的优先激活尚未在已知 TOXO 感染的 SCZ 患者中得到证实。此外，越来越多的文献表明，SCZ 患者大脑中 KYNA 水平升高，尽管这些患者的 TOXO 状态尚未得到调查。 TOXO 的进化导致了微妙的行为功能障碍，导致受感染的啮齿动物减少对猫的恐惧和精神运动减慢。在 TOXO 阳性的 SCZ 患者中，我们的试验数据表明神经处理速度减慢，表现为声惊吓反应潜伏期延长和认知测试受损。 该项目将研究以下假设：SCZ 中的慢性 TOXO 感染导致免疫介导的 KYN 通路激活，并且该通路激活与 TOXO 阳性 SCZ 中的神经处理减慢和认知缺陷相关。为了实现以下目标，我们将评估 VA 队列中 SCZ 患者和健康对照的 TOXO 免疫球蛋白 G 抗体 (IgG) 抗体滴度以及犬尿氨酸代谢物和 IFN¿ 的血浆水平。我们将通过比较四组（每组 38 名受试者）来检查这些神经免疫生物标志物与声惊吓反应、P50 门控和认知功能测试分数的关系：1) TOXO 阳性 SCZ，2) TOXO 阴性 SCZ，3) TOXO 阳性对照，4) TOXO 阴性对照。我们还提出了对血浆和脑脊液中 KYN 通路的新初步分析。规范目标 1：与 TOXO 阴性 SCZ 受试者以及患有或不患有 TOXO 的对照 (CON) 受试者相比，测量 TOXO 血清阳性 SCZ 受试者中 KYN 通路的激活情况。该途径的激活将通过 KYN、KYNA、色氨酸 (Trp) 和诱导 KYN 代谢的细胞因子 IFN¿ 的测定进行测试。探索性目标 1a：检查配对历史样本中 KYN 通路测量值的血浆和脑脊液 (CSF) 水平之间的相关性。我们假设血浆和脑脊液测量值将显着相关。规格目标 2：与 CON 受试者相比，测试 TOXO 感染对 SCZ 中以声惊潜伏期为指标的神经处理速度、P50 门控受损以及认知功能的影响。探索性目标 3：检查 KYN 通路激活是否可以预测惊吓潜伏期减慢、P50 门控受损和认知受损，以及它是否与 TOXO 状态相互作用。