Neuronal Latency and Toxoplasma

项目摘要 神经元很难被免疫系统识别，这对神经趋化能力有贡献。 病原体持续存在于中枢神经系统，但有证据表明T细胞可以促进这些病原体的清除 有机体。对于弓形虫寄生虫来说，T细胞产生细胞因子干扰素-对 中枢神经系统中的抵抗，因为它激活造血细胞和非造血细胞来控制 速殖子(裂殖期)感染阶段。相反，作为对细胞压力的反应，弓形虫转化为 潜伏的缓殖体期，并在神经元中形成长期存活的包囊。缺乏针对潜伏者的治疗方法 弓形虫的发育阶段是控制这种感染的重要障碍。目前的教条认为 因为这一阶段是在神经元中，它逃避了免疫监视，并确保了慢性。然而，还有 越来越多的证据表明，寄主和寄生虫之间在中枢神经系统发生了更活跃的战斗。这些 观察表明，产生干扰素-的T细胞激活神经元以控制弓形虫，但 这种寄生虫之所以持续存在，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，比较了速殖子和缓殖子的特异性反应 提示囊肿特异性CD8T细胞的效应器功能降低。为了了解弓形虫是怎样的 在神经元中识别以及寄生虫如何逃避监视，新的转基因报告系统 寄生虫将与宿主记者相结合，追踪体内受感染神经元的命运。其他内容 研究将确定干扰素-对神经元的影响，实时成像研究将可视化相互作用 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。 这些研究的发现将对理解CD8 T细胞如何 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和 神经炎症性疾病。

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.