Neuronal Latency and Toxoplasma

神经元潜伏期和弓形虫

• 批准号: 10793126
• 负责人: CHRISTOPHER A HUNTER
• 金额: $ 4.1万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-23 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10793126
• 关键词: Affect; Antigens; CD8-Positive T-Lymphocytes; Cell Communication; Cells; Cellular Stress; Central Nervous System; Chronic; Cyst; Data; Data Set; Dissection; Ensure; Enterobacteria phage P1 Cre recombinase; Gene Expression Profiling; Goals; Hematopoietic; Immune Evasion; Immune system; Immunologic Surveillance; Immunologic Tests; Immunologics; In Vitro; Infection; Interferon Type II; Interferons; Lasers; Lead; Lytic; MHC Class I Genes; Maps; Mediating; Microglia; Modeling; Neurons; Organism; Parasite Control; Parasites; Pathway interactions; Phenotype; Population; Process; Production; Reporter; Reporter Genes; Resistance; STAT1 gene; System; T-Cell Activation; T-Lymphocyte; Testing; Time; Toxoplasma; Toxoplasma gondii; Transgenic Organisms; Visualization; antimicrobial; candidate identification; cytokine; effector T cell; exhaust; imaging study; in vivo; in vivo imaging; infection management; intravital imaging; mouse model; multiphoton imaging; neuroinflammation; neurotropic; novel; novel therapeutics; pathogen; response; targeted treatment; transcription factor

Project Summary Neurons are poorly recognized by the immune system which contributes to the ability of neurotropic pathogens to persist in the CNS but there is evidence that T cells can promote clearance of these organisms. For the parasite Toxoplasma gondii, T cell production of the cytokine IFN- is important for resistance in the CNS because it activates hematopoietic and non-hematopoietic cells to control the tachyzoite (lytic) stage of the infection. Conversely, in response to cellular stress T. gondii transforms to the latent bradyzoite stage and forms long lived cysts in neurons. The lack of therapies that target the latent stage of T. gondii is a significant impediment to the management of this infection. Current dogma holds that because this stage is in neurons it evades immune surveillance and ensures chronicity. However, there is accumulating evidence of a more active battle between the host and parasite in the CNS. These observations indicate that T cell production of IFN- activates neurons to control T. gondii but the ability of this parasite to persist may be because bradyzoites evade recognition and/or modulate cyst specific responses. In support of this idea, comparisons between tachyzoite and bradyzoite specific responses suggest that cyst-specific CD8+ T cells have reduced effector functions. To understand how T. gondii is recognized in neurons and how the parasite can evade surveillance, novel transgenic reporter systems for parasites will be combined with host reporters to track the fate of infected neurons in vivo. Additional studies will determine the impact of IFN- on neurons and live imaging studies will visualize interactions between T cells and infected neurons and if this results in parasite clearance or evasion of T cell activities. The findings that emerge from these studies will have a significant impact on understanding how CD8+ T cell-neuron interactions lead to pathogen control and will be relevant to other neurotropic infections and neuroinflammatory conditions.

项目概要 神经元很难被免疫系统识别，这有助于神经营养的能力 病原体在中枢神经系统中持续存在，但有证据表明 T 细胞可以促进这些病原体的清除 有机体。对于弓形虫来说，T 细胞产生细胞因子 IFN- 对于 中枢神经系统中的抵抗，因为它激活造血和非造血细胞来控制 感染的速殖子（裂解）阶段。相反，为了应对细胞应激，弓形虫会转变为 潜伏的缓殖子阶段并在神经元中形成长寿命的包囊。缺乏针对潜在的治疗方法 弓形虫的阶段是控制这种感染的一个重大障碍。当前的教条认为 因为这个阶段是在神经元中，所以它可以逃避免疫监视并确保长期存在。然而，有 积累了中枢神经系统中宿主和寄生虫之间更活跃的战斗的证据。这些 观察表明，T 细胞产生 IFN-γ 会激活神经元控制弓形虫，但 这种寄生虫持续存在可能是因为缓殖子逃避识别和/或调节包囊特异性 回应。为了支持这一观点，速殖子和缓殖子特异性反应之间的比较 表明囊肿特异性 CD8+ T 细胞的效应功能降低。了解弓形虫的情况 在神经元中识别以及寄生虫如何逃避监视，新型转基因报告系统 寄生虫将与宿主报告基因结合，追踪体内受感染神经元的命运。额外的 研究将确定 IFN-γ 对神经元的影响，实时成像研究将相互作用可视化 T 细胞和受感染神经元之间的相互作用，以及这是否会导致寄生虫清除或逃避 T 细胞活动。 这些研究的结果将对理解 CD8+ T 的机制产生重大影响。 细胞-神经元相互作用导致病原体控制，并将与其他神经性感染和 神经炎症状况。