The role of kynurenine pathway activation in Toxoplasma-linked schizophrenia

描述(申请人提供)：精神分裂症(SCZ)被认为是遗传和环境因素累积相互作用的结果。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几十年。最近的两项荟萃分析发现，SCZ的慢性TOXO感染率有非常显著的上升。人类和啮齿动物是弓形虫的中间宿主，它进化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，并继续存在。弓形虫具有神经侵袭性，预计大多数感染者的大脑中会终生藏有弓形虫包囊，但这种寄生虫通常不会在免疫系统正常的人中引起明显的神经系统症状。弓形虫通过持续的免疫反应来控制，细胞因子干扰素在其中起着关键作用。干扰素由几种免疫细胞和脑胶质细胞产生，通过消耗TOXO必须来自宿主的色氨酸(Trp)来阻止TOXO的复制。干扰素通过酶控制的一系列步骤进入犬尿氨酸(KYN)和犬尿酸(KYNA)，沿着犬尿氨酸(KYN)途径分流色氨酸的降解，从而实现局部色氨酸的耗竭。Kyna反过来又是两个神经递质受体的拮抗剂，这两个受体被认为在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可导致SCZ的神经化学异常是可能的机制，但在已知TOXO感染的SCZ患者中尚未证实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，尽管这些患者的TOXO状态尚未被调查。弓形虫的进化导致了细微的行为障碍，导致受感染的啮齿动物减少了对猫的恐惧，精神运动减慢。在TOXO阳性的SCZ患者中，我们的试点数据表明，以声学惊吓反应潜伏期延长和认知测试损害为指标的神经处理放缓。本项目将研究慢性TOXO感染SCZ导致免疫介导的KYN通路激活的假说，以及该通路的激活与TOXO阳性SCZ的神经处理减慢和认知障碍有关。为了实现以下目标，我们将评估我们VA队列中的SCZ患者和健康对照组的TOXO免疫球蛋白G抗体(IgG)抗体效价以及血浆犬尿氨酸代谢产物和干扰素的水平。我们将通过比较四组每组38名受试者(1)TOXO阳性SCZ，2)TOXO阴性SCZ，3)TOXO阳性对照，4)TOXO阴性对照，来检验这些神经免疫生物标志物与听觉惊厥反应、P50门控和认知功能测试分数的关系。我们还对血浆和脑脊液中的KYN通路提出了新的初步分析。规范目标1：检测TOXO血清阳性的SCZ患者与TOXO阴性的SCZ患者和CON患者(CON)中KYN通路的激活情况。这一途径的激活将通过检测KYN、KYNA、色氨酸(Trp)和诱导KYN代谢的细胞因子干扰素来测试。探索性目标1a：在配对的历史样本中，检验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，血浆和脑脊液的测定将显著相关。规范目标2：测试TOXO感染对以听觉惊厥潜伏期为指标的神经加工速度、受损的P50门控的影响，以及与CON受试者相比对认知功能的影响。探索性目标3：检验惊厥潜伏期减慢、P50门控受损和认知受损是否通过KYN通路激活而被预测，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.