Neuronal Latency and Toxoplasma

神经元潜伏期和弓形虫

• 批准号: 10268235
• 负责人: CHRISTOPHER A HUNTER
• 金额: $ 74.89万
• 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/10268235
• 关键词: Affect; Antigens; CD8-Positive T-Lymphocytes; Cell Communication; Cells; Cellular Stress; Chronic; Cyst; Data; Data Set; Dissection; Ensure; Enterobacteria phage P1 Cre recombinase; Gene Expression Profiling; Goals; Hematopoietic; 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; Neuraxis; Neurons; Organism; Parasite Control; Parasites; Pathway interactions; Phenotype; Population; Process; Production; Reporter; Resistance; STAT1 gene; System; T-Lymphocyte; Testing; Time; Toxoplasma; Toxoplasma gondii; Transgenic Organisms; Tumor stage; antimicrobial; 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.

项目摘要 免疫系统对神经元的识别能力较差，这有助于嗜神经性免疫的能力。 病原体在CNS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。 有机体对于寄生虫弓形虫，T细胞产生细胞因子IFN-γ对于 因为它激活造血和非造血细胞以控制CNS中的耐药性， 感染的速殖子（溶解）阶段。相反，在细胞应激反应中，T.弓形虫转化为 潜伏的缓殖子期并在神经元中形成长寿命的包囊。缺乏针对潜在的 T期。弓形虫是控制这种感染的一个重大障碍。目前的教条认为， 因为这一阶段是在神经元中，它逃避免疫监视并确保慢性化。不过有 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IFN-γ的T细胞产生激活神经元以控制T。但弓形虫的能力 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， 应答为了支持这一观点，速殖子和缓殖子特异性反应之间的比较 表明囊肿特异性CD 8 + T细胞具有降低的效应子功能。了解T.弓形虫是 认识到在神经元和寄生虫如何可以逃避监视，新的转基因报告系统， 寄生虫将与宿主报告基因结合，以追踪体内受感染神经元的命运。额外 研究将确定IFN-γ对神经元的影响，实时成像研究将显示相互作用 在T细胞和受感染的神经元之间，如果这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CD 8 + T细胞如何在细胞内表达产生重大影响。 细胞-神经元相互作用导致病原体控制，并将与其他嗜神经性感染相关， 神经炎性疾病