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

弓形虫分泌蛋白（PSP7）致病性作用分析

• 批准号: 13J01218
• 负责人: 馬 知秀
• 金额: $ 1.15万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for JSPS Fellows
• 财政年份: 2013
• 资助国家: 日本
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13J01218/
• 关键词: Toxoplasma gondii; NFAT4; GRA6; CAMLG; chemokine; Calcineurin

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.

弓形虫感染会导致宿主细胞信号通路的共存和颠覆。这一过程涉及T.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。

项目成果

トキソプラズマ原虫の多型濃縮顆粒タンパク質GRA6による選択的NFAT4の活性化について 口頭発表。

口头报告弓形虫多态性富集颗粒蛋白 GRA6 选择性激活 NFAT4。

• 发表时间: 2015
• 作者: Nagai;M.;Aoki;H.;Sakoda;Y.;Kozasa;T.;Tominaga-Teshima;K.;Mine;J.;Abe Y.;Tamura;T.;Kobayashi;T.;Nishine;K.;Tateishi;K.;Suzuki;Y.;Fukuhara;M.;Ohmori;K.;Todaka;R.;Katayama;K.;Mizutani;T.;Nakamura;S.;Kida;H.;Shirai;J.;Ji Su Ma
• 通讯作者: Ji Su Ma

Selective and strain-specific NFAT4 activation by the Tbxoplasma gondli

Tbxoplasma gondli 选择性和菌株特异性 NFAT4 激活

• 发表时间: 2013
• 作者: Tamura;T.;Nagashima;N.;Ruggli;N.;Summerfield;A.;Kida;H.;Sakoda;Y.;馬 知秀
• 通讯作者: 馬 知秀