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

弓形虫感染导致宿主细胞信号转导通路的共选择和颠覆。该过程涉及T的放电。来自寄生虫分泌细胞器如棒状体和致密颗粒的弓形虫效应分子。我发现T.弓形虫多态性致密颗粒蛋白GRA6调节宿主转录因子活化T细胞核因子4（NFAT 4）的活化。GRA6过表达通过钙调节配体（CAMLG）稳健地和选择性地激活NFAT 4。感染野生型（WT），而不是GRA6缺陷型寄生虫诱导NFAT 4激活。此外，GRA6缺陷型寄生虫在局部感染中未能表现出完全的毒力，并且用NFAT抑制剂治疗WT小鼠减轻了WT寄生虫的毒力。值得注意的是，NFAT 4缺陷型小鼠表现出存活时间延长，CD 11 B+ Ly6 G+细胞向感染部位的募集减少，以及趋化因子如Cxcl 2和Ccl 2的表达受损。此外，由于GRA6 C末端的多态性，I型寄生虫感染导致比II型寄生虫显著更高的NFAT 4活化。总的来说，这些数据表明，T.弓形虫操纵宿主免疫反应，以菌株依赖的方式使寄生虫毒力最大化。

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.