Selective and strain-specific NFAT4 activation by the Toxoplasma gondii polymorphic dense granule protein GRA6.
Selective and strain-specific NFAT4 activation by the Toxoplasma gondii polymorphic dense granule protein GRA6.
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DOI：
10.1084/jem.20131272
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发表时间：
2014-09-22
期刊：
影响因子：
--
通讯作者：
Yamamoto M
中科院分区：
文献类型：
--
作者：
Ma JS;Sasai M;Ohshima J;Lee Y;Bando H;Takeda K;Yamamoto M
Ma等人表明，弓形虫多态性致密颗粒蛋白GRA6触发宿主转录因子NFAT 4的激活，从而影响宿主免疫应答并使寄生虫毒力最大化。弓形虫感染导致宿主细胞信号转导通路的共选择和颠覆。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。我们报告说，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缺陷型小鼠表现出延长的存活期，减少CD11b+ Ly6G+细胞向感染部位的募集，以及趋化因子如Cxcl2和Ccl2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，我们的数据表明，GRA6依赖性NFAT 4激活是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。
Ma et al. show that the Toxoplasma gondii polymorphic dense granule protein GRA6 triggers the activation of the host transcription factor NFAT4, thus affecting the host immune response and maximizing parasite virulence. 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. We report 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 wild-type (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 CD11b+ 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, our 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.
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影响因子：
64.8
作者：
JAIN, JN;MCCAFFREY, PG;RAO, A
通讯作者：
RAO, A
影响因子：
20.1
作者：
Bushdid, PB;Osinska, H;Yutzey, KE
通讯作者：
Yutzey, KE
DOI：
10.1073/pnas.1220272110
发表时间：
2013-05-21
影响因子：
11.1
作者：
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通讯作者：
Robey, Ellen A.
影响因子：
4
作者：
Fazaeli, A;Carter, PE;Pennington, TH
通讯作者：
Pennington, TH
影响因子：
1.3
作者：
Dubey, J. P.;Gennari, S. M.;Su, C.
通讯作者：
Su, C.