期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 211, 期 10, 页码 2013-2032出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20131272
关键词
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资金
- Ministry of Education, Culture, Sports, Science and Technology, and Takeda Science Foundation
- Senri Life Science Foundation
- Tokyo Biochemical Research Foundation
- Research Foundation for Microbial Diseases of Osaka University
- Asahi Glass Foundation
- Sumitomo Foundation
- Sagawa Foundation of Promotion of Cancer Research
- Suzuken Memorial Foundation
- Osaka Cancer Research Foundation
- Daiichi-Sankyo Foundation of Life Science
- Uehara Memorial Foundation
- Ichiro Kanehara Foundation
- Inoue Research Award
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Kanae Fundation for the Promorion of Medical Science
- Japan Intractable Disease Research Foundation
- Kao Foundation for Arts and Sciences
- Japan Society for the Promotion of Science for Young Scientists
- Grants-in-Aid for Scientific Research [24390120, 26860189] Funding Source: KAKEN
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 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 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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