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中慢性TOXO感染率显著升高。人类和啮齿动物是TOXO的中间宿主，TOXO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。TOXO是一种神经侵入性疾病，预计大多数感染者都携带T。弓形虫囊肿在他们的大脑中生活，但寄生虫通常不会引起明显的神经系统症状的人与正常的免疫系统。TOXO通过持续的免疫反应来控制，其中细胞因子干扰素γ（IFN？）起着关键作用。干扰素由几种免疫细胞以及脑神经胶质细胞产生，并通过耗尽氨基酸色氨酸（Trp）来防止TOXO复制，而TOXO必须来自宿主。干扰素通过将Trp降解沿着犬尿氨酸（KYN）途径通过酶控制的一系列步骤分流成KYN和犬尿烯酸（KYNA）来实现局部Trp消耗。KYNA反过来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（α 7 nACh）受体。因此，存在TOXO可引起导致SCZ的神经化学异常的合理机制，但尚未在已知TOXO感染的SCZ患者中证实KYN通路的优先激活。此外，越来越多的文献表明，SCZ患者的大脑中KYNA水平升高，尽管尚未研究这些患者的TOXO状态。TOXO进化为诱导微妙的行为功能障碍，导致受感染的啮齿动物对猫的恐惧减少，精神发育迟缓。在TOXO阳性的SCZ患者中，我们的初步数据表明神经处理减慢，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SCZ中的慢性TOXO感染导致免疫介导的KYN通路激活的假设，并且该通路激活与TOXO阳性SCZ中观察到的神经处理和认知缺陷减慢相关。为了实现以下目标，我们将评估VA队列中的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 ²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和声惊吓反应、P50门控和认知功能测试评分的关系：1）TOXO阳性SCZ，2）TOXO阴性SCZ，3）TOXO阳性对照，4）TOXO阴性对照。我们还提出了血浆和CSF中KYN途径的新的初步分析。规范目标1：测量TOXO血清阳性SCZ受试者与TOXO阴性SCZ受试者和有和无TOXO的对照（CON）受试者相比的KYN通路活化。将通过KYN、KYNA、色氨酸（Trp）和诱导KYN代谢的细胞因子IFN？测定来测试该途径的激活。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CSF指标显著相关。规范目标2：与CON受试者相比，测试TOXO感染对SCZ中神经处理速度（以声惊吓潜伏期为指标）、受损P50门控和认知功能的影响。探索性目标3：检查KYN通路激活是否可预测惊吓潜伏期减缓、P50门控受损和认知受损，以及是否与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.