GRA24-Based DNA Vaccine Prolongs Survival in Mice Challenged With a Virulent Toxoplasma gondii Strain
GRA24-Based DNA Vaccine Prolongs Survival in Mice Challenged With a Virulent Toxoplasma gondii Strain
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基于 GRA24 的 DNA 疫苗可延长遭受有毒弓形虫菌株攻击的小鼠的生存期
DOI：
10.3389/fimmu.2019.00418
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发表时间：
2019
影响因子：
7.3
通讯作者：
Lu Shaohong
中科院分区：
文献类型：
--
作者：
Zheng Bin;Lou Di;Ding Jianzu;Zhuo Xunhui;Ding Haojie;Kong Qingming;Lu Shaohong
由于缺乏有效的药物和疫苗，弓形虫在广泛的中间宿主中引起感染，并且仍然是世界范围内的威胁性疾病。致密颗粒蛋白24（Dense granule protein 24，GRA 24）是一种新的重要的毒力因子，它从寄主细胞的液泡中转移到细胞核中调控基因的表达。在本研究中，生物信息学分析表明，GRA 24与表面抗原1（SAG 1）相比，具有较高的B细胞和T细胞表位评分，SAG 1已被研究为有前途的疫苗候选者。将pVAX 1-GRA 24作为DNA疫苗肌肉注射给Balb/c小鼠，评价诱导的免疫反应。pVAX 1-GRA 24在免疫后6周诱导高水平的混合Th 1/Th 2细胞因子。抗体测定、细胞因子[干扰素γ（IFN-γ）、白细胞介素（IL）-12、IL-4、IL-10]、抗原特异性淋巴细胞增殖、CD 4+和CD 8 + T淋巴细胞以及细胞毒性T淋巴细胞活性表明，用pVAX 1-GRA 24免疫的小鼠产生特异性体液和细胞免疫应答。pVAX 1-GRA 24免疫组中干扰素调节因子8（IRF 8）、核因子κ B（NF-κB）和T-Box 21（T-bet）的表达水平显著高于对照组。与对照组相比，pVAX 1-GRA 24免疫组小鼠的存活时间显著延长（24.6 ± 5.5天），对照组小鼠在T.弓形虫攻毒（P < 0.05）。本研究结果表明，pVAX 1-GRA 24诱导T. gondii特异性免疫应答，因此代表了治疗弓形虫病的有希望的候选疫苗。
Toxoplasma gondii causes infections in a wide range of intermediate hosts and remains a threatening disease worldwide because of the lack of effective drugs and vaccines. Dense granule protein 24 (GRA24) is a novel essential virulence factor that is transferred into the nucleus of host cells from the parasitophorous vacuole to regulate gene expression. In the present study, bioinformatic analysis showed that GRA24 had a high score for B-cell and T-cell epitopes compared with surface antigen 1 (SAG1), which has been studied as a promising vaccine candidate. As a DNA vaccine, pVAX1-GRA24 was injected intramuscularly into BALB/c mice and the induced immune response was evaluated. pVAX1-GRA24 induced high levels of a mixed Th1/Th2 cytokines at 6 weeks after immunization. Antibody determinations, cytokines [interferon gamma (IFN-γ), interleukin (IL)-12, IL-4, IL-10], antigen-specific lymphocyte proliferation, CD4+ and CD8+ T lymphocytes, and cytotoxic T lymphocyte activity showed that mice immunized with pVAX1-GRA24 produced specific humoral and cellular immune responses. The expression levels of interferon regulatory factor 8 (IRF8), nuclear factor kappa B (NF-κB), and T-Box 21 (T-bet) were significantly higher in the pVAX1-GRA24 immunization group than in the control groups. Survival times were prolonged significantly (24.6 ± 5.5 days) in the mice immunized with pVAX1-GRA24 compared with the mice in the control groups, which died within 7 days of T. gondii challenge (p < 0.05). The results of the present study showed that pVAX1-GRA24 induced a T. gondii-specific immune response and thus represents a promising candidate vaccine to treat toxoplasmosis.