抗弓形虫慢性感染的CD8+T淋巴细胞消耗及其拯救的作用机制研究

Zoonotic toxoplasmosis caused by Toxoplasma gondii is a serious threat to human health, it also causes significant economic losses to animal production. The main reason that animal and human toxoplasmosis has not been controlled well is the insufficiency in its basic research, particularly it is yet to understand the mechanism underlying the immunity to T. gondii. Therefore, using the T. gondii genotype II (PRU) strain as the model genotype, and the mice which is susceptible intermediate host as the model animal, the objectives of the present project are focused on how immune exhaustion specifically mediates attribution of CD8+ T cells, and how to rescue of dysfunctional CD8+ T-cell response during chronic infetion, by using an established animal model that chronic infetion with PRU strain, to characterize inhibitory molecules expressed in CD8+ T-cells, and to resolve the progresses mediated CD8+ T-cell dysfunction, by inoculation of eukaryotic plasmids expressing IL-15+IL-21, IL-2 and IL-15+IL-7 to screen the proper therapeutic cytokines against T. gondii, and to resolve the effects on antigen-specific T cells in chronically infected mice depending on the timing and daily low-dose cytokines therapy, by therapeutic use of cytokines alone or/and combinatorial approaches with inhibitory molecules blockade, to clarify the mechanism and the effective regimen involved in reinvigorating exhausted CD8+ T-cells. The expected results would contribute to better understand the T. gondii-host interaction and relationship relating to immunity and pathogenesis, and also would contribute to design rational strategies for developing immunotherapies for chronic infections.

人兽共患弓形虫病严重危害人类和动物的生命及健康。弓形虫病尚未得到有效防制的主要原因是对弓形虫病基础研究不足，特别是宿主抗弓形虫感染免疫机制尚不清楚。本项目以小鼠感染弓形虫II型（PRU虫株）动物模型为研究对象，开展弓形虫慢性感染引起CD8+ T淋巴细胞消耗和拯救作用机制研究。通过建立小鼠慢性弓形虫感染模型，鉴定CD8+ T淋巴细胞表面抑制受体分子，解析各表面抑制分子对引起CD8+ T淋巴细胞消耗的作用机制。通过对构建的表达细胞因子IL-15+IL-21、IL-2和IL-15+IL-7真核表达载体进行不同时间段、不同剂量的免疫注射治疗，解析抗弓形虫感染的免疫治疗细胞因子治疗效应。通过细胞因子以及与抗表面抑制受体抗体的单独或联合治疗，阐明拯救CD8+ T淋巴细胞消耗的作用机制以及最佳作用途径。预期研究成果将为弓形弓形虫病的防控提供更充分的科学依据同时为弓形虫药物的开发和疫苗的研制奠定理论基础。

人兽共患弓形虫病严重危害人类和动物的生命及健康。弓形虫病尚未得到有效防制的主要原因是对弓形虫病基础研究不足，特别是宿主抗弓形虫感染免疫机制尚不清楚。本项目以小鼠感染弓形虫II型（PRU虫株）动物模型为研究对象，开展了弓形虫慢性感染引起CD8+ T淋巴细胞消耗和拯救作用机制研究。通过建立小鼠慢性弓形虫感染模型，鉴定了CD8+ T淋巴细胞表面抑制受体分子，解析了表面抑制分子Tim3对引起CD8+ T淋巴细胞消耗的作用机制。通过对构建的表达细胞因子IL-15+IL-21、IL-2和IL-15+IL-7真核表达载体进行不同时间段、不同剂量的免疫注射治疗，解析了抗弓形虫感染的免疫治疗细胞因子治疗效应。通过细胞因子以及与抗表面抑制受体抗体的单独或联合治疗，阐明了拯救CD8+ T淋巴细胞消耗的作用机制以及最佳作用途径。预期研究成果将为弓形弓形虫病的防控提供更充分的科学依据，同时为弓形虫药物的开发和疫苗的研制奠定理论基础。