トキソプラズマ原虫分泌蛋白質（ＰＳＰ＃７）の病原性における役割の解析

刚地弓形虫感染导致宿主细胞信号通路的共选择和颠覆。这一过程涉及弓形虫效应分子从寄生虫分泌细胞器（如虫体和致密颗粒）中排出。我发现弓形虫多态致密颗粒蛋白GRA6调控活化T细胞宿主转录因子核因子4 （NFAT4）的活化。GRA6过表达并通过钙调节配体（CAMLG）选择性激活NFAT4。感染野生型（WT）而非缺乏gra6的寄生虫诱导NFAT4激活。此外，缺乏gra6的寄生虫在局部感染中未能表现出完全的毒力，用NFAT抑制剂治疗WT小鼠可以减轻WT寄生虫的毒力。值得注意的是，nfat4缺陷小鼠的存活时间延长，感染部位的cd11b + Ly6G+细胞募集减少，趋化因子如Cxcl2和Ccl2的表达受损。此外，由于GRA6的C端多态性，感染I型寄生虫的NFAT4活性明显高于II型寄生虫。总的来说，这些数据表明，gondii操纵宿主免疫反应以菌株依赖的方式最大化寄生虫毒力需要gra6依赖性NFAT4激活。

Toxoplasma gondii infection results in co-option and subversion of host cellular signaling pathways. This process involves discharge of T. gondii effector molecules from parasite secretory organelles such as rhoptries and dense granules. I found that the T. gondii polymorphic dense granule protein GRA6 regulates activation of the host transcription factor nuclear factor of activated T cells 4 (NFAT4). GRA6 overexpression robustly and selectively activated NFAT4 via calcium modulating ligand (CAMLG). Infection with wildtype (WT) but not GRA6-deficient parasites induced NFAT4 activation. Moreover, GRA6-deficient parasites failed to exhibit full virulence in local infection, and the treatment of WT mice with an NFAT inhibitor mitigated virulence of WT parasites. Notably, NFAT4-deficient mice displayed prolonged survival, decreased recruitment of CD11 b+ Ly6G+ cells to the site of infection, and impaired expression of chemokines such as Cxcl2 and Ccl2. In addition, infection with type I parasites culminated in significantly higher NFAT4 activation than type II parasites due to a polymorphism in the C terminus of GRA6. Collectively, these data suggest that GRA6-dependent NFAT4 activation is required for T. gondii manipulation of host immune responses to maximize the parasite virulence in a strain-dependent manner.