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通路的选择性和颠覆。这一过程涉及弓形虫效应器分子从寄生虫的分泌细胞器，如棒状体和致密颗粒中排出。我发现弓形虫多态致密颗粒蛋白GRA6调节宿主转录因子活化T细胞核因子4(NFAT4)的激活。GRA6的高表达通过钙调节配体(CAMLG)选择性地激活NFAT4。感染野生型(WT)而不是GRA6缺乏的寄生虫可诱导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，CD11b+Ly6G+细胞到感染部位的募集减少，以及Cxcl2和CCL2等趋化因子的表达受损。此外，由于GRA6 C末端的多态，感染I型寄生虫的NFAT4活性显著高于II型寄生虫。总之，这些数据表明，依赖于GRA6的NFAT4激活是弓形虫操纵宿主免疫反应以依赖菌株的方式最大化寄生虫毒力所必需的。

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.