Toxoplasma gondii Regulation of Host GABAergic Signaling

 描述（由申请人提供）：癫痫发作是中枢神经系统感染和炎症患者常见的危及生命的并发症。在这些个体中，癫痫发作由于多种原因而发展，包括血脑屏障的破坏、离子稳态的变化和/或炎性蛋白质（如细胞因子和抗体）的丰度增加。但是，大脑中的这些变化如何改变引起癫痫样活动的突触连接和神经传递，在很大程度上是未知的。弓形虫（Toxoplasma gondii）感染了世界上大约三分之一的人口。大多数人没有症状，因为寄生虫潜伏在大脑和其他组织中。但是，当寄生虫重新激活并且宿主免疫反应无法控制寄生虫复制或失调导致免疫介导的组织破坏时，免疫功能低下或在子宫内感染的个体会发生弓形虫病。如果再激活发生在大脑中，所产生的弓形虫脑炎表现为各种各样的 神经系统后遗症包括癫痫使用弓形虫脑炎的小鼠模型，我们的数据表明弓形虫特异性地改变了位于GABA能突触的关键蛋白质的分布。GABA能突触连接的这种变化导致小鼠发生癫痫发作，因为这些突触对于控制大脑中信息传递的流量和时间至关重要。这项工作将定义这些蛋白质是如何错误定位的（目标1），确定GABA能蛋白错误定位中炎性细胞的作用（目标2），并确定影响GABA能蛋白定位和癫痫发作的寄生虫因素（目标3）。这项工作的长期目标是确定弓形虫感染者的癫痫发作是如何发展的，并利用这些信息来产生新的疗法来治疗这些患者和其他感染诱导的癫痫发作患者。

 DESCRIPTION (provided by applicant): Seizures are a common and life-threatening complication of individuals suffering from infections and inflammation in the central nervous system. In these individuals, seizures develop due to a variety of reasons including breakdown of the blood-brain barrier, changes in ionic homeostasis, and/or increased abundance of inflammatory proteins such as cytokines and antibodies. But, how these changes in the brain alter synaptic wiring and neurotransmission that cause epileptiform activity is largely unknown. The protozoan parasite Toxoplasma gondii infects approximately one-third of the world's population. Most people are asymptomatic because the parasite resides latently within brain and other tissues. But individuals who are immunocompromised or are infected in utero develop toxoplasmosis when the parasite reactivates and the host immune response is unable to control parasite replication or is dysregulated leading immune-mediated tissue destruction. If reactivation occurs in the brain, the resulting toxoplasmic encephalitis presents with a variety of neurological sequelae that includes seizures. Using a murine model for toxoplasmic encephalitis our data indicates that Toxoplasma specifically alters the distribution of key proteins that localie to GABAergic synapses. This change in GABAergic synaptic connectivity causes the mice to develop seizures because these synapses are critical for controlling the flow and timing of information transfer in the brain. This work will define how these proteins are mislocalized (Aim 1), determine the role of inflammatory cells in GABAergic protein mislocalization (Aim 2), and identify the parasite factors that affect GABAergic protein localization and onset of seizures (Aim3). The long-term goal of this work is to determine how seizures develop in Toxoplasma-infected individuals and use this information to generate novel therapies to treat these patients and others suffering from infection-induced seizures.