The role of kynurenine pathway activation in Toxoplasma-linked schizophrenia

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引起的。在SCZ的发病机制中，细胞内寄生虫弓形虫（TOXO）感染的证据已经积累了几十年。最近的两项荟萃分析发现，SCZ慢性弓形虫感染率显著升高。人类和啮齿动物是弓形虫的中间宿主，弓形虫进化出复杂的生命周期和独特的机制，以逃避宿主的破坏，改变宿主的行为，并继续存在。弓形虫是神经侵入性的，大多数感染者预计会在其大脑中终生携带弓形虫囊肿，但这种寄生虫通常不会在免疫系统正常的人身上引起明显的神经系统症状。弓形虫是通过持续的免疫反应来控制的，其中细胞因子干扰素γ （IFN¿）起着关键作用。IFN¿由几种免疫细胞和脑胶质细胞产生，并通过耗尽TOXO必须从宿主获得的氨基酸色氨酸（Trp）来阻止TOXO的复制。IFN通过酶控制的一系列进入KYN和KYNA的步骤，沿着犬尿氨酸（KYN）途径分流Trp降解，从而实现局部Trp消耗。KYNA是两种神经递质受体的拮抗剂，这两种受体被认为在SCZ中起关键作用：谷氨酸受体的n -甲基- d -天冬氨酸（NMDA）亚型和α - 7烟碱乙酰胆碱（a7nACh）受体。因此，弓形虫引起神经化学异常导致SCZ的机制似乎是合理的，但在已知感染弓形虫的SCZ患者中，KYN通路的优先激活尚未得到证实。此外，越来越多的文献表明，SCZ患者的大脑中KYNA水平升高，尽管这些患者的TOXO状态尚未被调查。弓形虫进化后会诱发细微的行为障碍，导致受感染的啮齿动物对猫的恐惧减少，精神运动减慢。在弓形虫阳性的SCZ患者中，我们的试验数据表明，通过延长声惊吓反应的潜伏期，神经处理减慢，认知测试受损。本项目将研究慢性TOXO感染SCZ导致免疫介导的KYN通路激活的假设，并且该通路的激活与TOXO阳性SCZ的神经加工减慢和认知缺陷有关。为了实现以下目标，我们将在我们的VA队列中评估SCZ患者和健康对照者的弓形虫免疫球蛋白G抗体（IgG）抗体滴度和血浆犬尿氨酸代谢物和IFN¿水平。我们将通过比较四组（每组38人）来研究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)弓形虫阳性SCZ， 2)弓形虫阴性SCZ， 3)弓形虫阳性对照，4)弓形虫阴性对照。我们还提出了血浆和脑脊液中KYN通路的新的初步分析。特别目标1：测量在血清弓形虫阳性的SCZ受试者中，与弓形虫阴性的SCZ受试者和有或没有弓形虫的对照组（CON）受试者相比，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¿的测定来测试。探索性目的1a：检查配对历史样本中KYN通路测量的血浆和脑脊液（CSF）水平之间的相关性。我们假设血浆和脑脊液测量将显著相关。具体目标2：测试弓形虫感染对以声惊吓潜伏期为指标的神经处理速度的影响，对受损P50门控的影响，以及对SCZ与CON受试者认知功能的影响。探索性目的3：研究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。

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.