Development of DNA vaccine against intracellular protozoa bored on ubiquitin-proteasome system

基于泛素-蛋白酶体系统的细胞内原虫DNA疫苗的研制

• 批准号: 16017276
• 负责人: HIMENO Kunisuke
• 金额: $ 9.6万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16017276/
• 关键词: intracellular protozoa; DNA vaccine; gene gun; ubiquitin; ubiquitin-proteasome; CD84T cell; proteasome KO mice; proteasome inhibitor; 細胞内寄生原虫; ユビキチンプロテアソーム系; トキソプラズマ; SAG-1; ユビキチン融合遺伝子; PA28ノックアウトマウス

The intracellular protozoan Toxoplasma gondii (T.gondii) is a major opportunistic pathogen in the immunocompromized patient population worldwide. Among the vaccine candidates, the SAG1 protein is the best characterized. This 30-kDa protein is the major surface antigen of T gondii tachyzoites, is highly conserved in T gondii strains, inducing high antibody levels in humans, and is recognized by all the serum samples from infected subjects. CD8^+ T cells play an essential role in the protection against a highly virulent RH strain of T gondii. Some CD8^+ CTL epitopes included in the SAG1 had been defined. However, most vaccine trials including DNA vaccine have resulted in failure agaist the high virulent RH strain except against the cultured and attenuated strain. In the present study, we constructed the vaccine vector encoding ubiquitinated SAG1 which is expected to be processed by "ubiquitin-proteasome pathway" and then be led to MHC class I molecules, resulting in the activation of SAG1-specific CD8^+ T cells.Mice immunized with the chimeric DNA developed potent protective immunity against Toxoplasma mediated by SAG1-specific CD8^+T cells, while mice immunized with SAG1 gene alone did not. The enhanced immunity was dependent on the ubiquitination of SAG1 that enabled it to be efficiently processed by the proteasome pathway resulting in efficient induction of specific CD8^+T cells. The immunity was dependent on immunoproteasome LMP7 but independent on PA28a/b, a proteasome activator.

细胞内原生动物弓形虫（T.gondii）是全世界免疫功能低下患者群体中的主要机会病原体。在候选疫苗中，SAG1 蛋白的特征最为明确。这种 30 kDa 的蛋白是弓形虫速殖子的主要表面抗原，在弓形虫菌株中高度保守，可在人体中诱导高抗体水平，并被感染受试者的所有血清样本所识别。 CD8^+ T 细胞在防御高毒力 RH 弓形虫菌株中发挥重要作用。 SAG1 中包含的一些 CD8^+ CTL 表位已被定义。然而，大多数疫苗试验，包括DNA疫苗，都导致除了针对培养和减毒株之外的针对高毒力RH株的失败。在本研究中，我们构建了编码泛素化SAG1的疫苗载体，期望通过“泛素-蛋白酶体途径”加工，然后产生MHC I类分子，从而激活SAG1特异性CD8^+ T细胞。用嵌合DNA免疫的小鼠对SAG1特异性CD8^+T细胞介导的弓形虫产生了有效的保护性免疫，而单独用SAG1基因免疫的小鼠却没有。增强的免疫力依赖于 SAG1 的泛素化，使其能够被蛋白酶体途径有效加工，从而有效诱导特定的 CD8^+T 细胞。免疫依赖于免疫蛋白酶体LMP7，但不依赖于蛋白酶体激活剂PA28a/b。

项目成果

WSX-1 is required for resistance to Trypanosoma cruzi infection by regulation pro-inflammatory cytokine production.

WSX-1 是通过调节促炎细胞因子的产生来抵抗克氏锥虫感染所必需的。

• 发表时间: 2003
• 期刊: Immunity 19(5)
• 作者: Toyooka;K.;et al.;Kaneko O;Yano K;Kaneko 0;Yano K;Arakawa T;Sawasaki T;Arakawa T;Sawasaki T;Arakawa T;Kaneko O;Rungruang T;Sattabongkot J;Li F;Li F;Ling IT;Tsuboi T;Li F;Kongkasuriyachai D;Win TT;Duan X.et al.;Ishii K. et al.;Duan X.et al.;Ishii K. et al.;Duan X.et al.;Ishii K. et al.;Hisaeda H. et al.;Zhang M. et al.;Hisaeda H. et al.;Hisaeda H. et al.;Zhang M. et al.;Hisaeda H. et al.;Hisaeda H. et al.;Zhang M. et al.;Zhang M. et al.;Hisaeda H. et al.;Okamoto M. et al.;Obata C. et al.;Onishi K. et al.;Yamanaka A. et al.;Zhang M. et al.;Li Y.et al.;Hisaeda H. et al.;Okamoto M. et al.;Obata C. et al.;Onishi K. et al.;Yamanaka A. et al.;Zhang M. et al.;Li Y.et al.;Hisaeda H. et al.;Onishi K. et al.;Yamanaka A. et al.;Hamano S. et al.;Seki YI. et al.;Katunuma N. et al.;Hisaeda H. et al.;Sakai T. et al.;Sakai T. et al.;Hamano S. et al.
• 通讯作者: Hamano S. et al.

Toll-Like Receptor 4 Mediates the Antitumor Host Response Induced by a 55-Kilodalton Protein Isolated from Aeginetia indica L.,a Plant.

Toll 样受体 4 介导从 Aeginetia indica L. 植物中分离的 55 千道尔顿蛋白质诱导的抗肿瘤宿主反应。

• 发表时间: 2004
• 期刊: Clin Diagn Lab Immunol. 11・3
• 作者: Toyooka;K.;et al.;Kaneko O;Yano K;Kaneko 0;Yano K;Arakawa T;Sawasaki T;Arakawa T;Sawasaki T;Arakawa T;Kaneko O;Rungruang T;Sattabongkot J;Li F;Li F;Ling IT;Tsuboi T;Li F;Kongkasuriyachai D;Win TT;Duan X.et al.;Ishii K. et al.;Duan X.et al.;Ishii K. et al.;Duan X.et al.;Ishii K. et al.;Hisaeda H. et al.;Zhang M. et al.;Hisaeda H. et al.;Hisaeda H. et al.;Zhang M. et al.;Hisaeda H. et al.;Hisaeda H. et al.;Zhang M. et al.;Zhang M. et al.;Hisaeda H. et al.;Okamoto M. et al.
• 通讯作者: Okamoto M. et al.

Malaria vaccines that inhibit parasite spread by mosquito vectors

抑制蚊媒传播寄生虫的疟疾疫苗

• 发表时间: 2003
• 期刊: Recent Research Developments in Immunology 5
• 作者: Toyooka;K.;et al.;Kaneko O;Yano K;Kaneko 0;Yano K;Arakawa T;Sawasaki T;Arakawa T;Sawasaki T;Arakawa T;Kaneko O;Rungruang T;Sattabongkot J;Li F;Li F;Ling IT;Tsuboi T;Li F;Kongkasuriyachai D;Win TT;Duan X.et al.;Ishii K. et al.;Duan X.et al.;Ishii K. et al.;Duan X.et al.;Ishii K. et al.;Hisaeda H. et al.;Zhang M. et al.;Hisaeda H. et al.;Hisaeda H. et al.;Zhang M. et al.;Hisaeda H. et al.;Hisaeda H. et al.;Zhang M. et al.;Zhang M. et al.;Hisaeda H. et al.;Okamoto M. et al.;Obata C. et al.;Onishi K. et al.;Yamanaka A. et al.;Zhang M. et al.;Li Y.et al.;Hisaeda H. et al.;Okamoto M. et al.;Obata C. et al.;Onishi K. et al.;Yamanaka A. et al.;Zhang M. et al.;Li Y.et al.;Hisaeda H. et al.;Onishi K. et al.;Yamanaka A. et al.;Hamano S. et al.;Seki YI. et al.;Katunuma N. et al.;Hisaeda H. et al.
• 通讯作者: Hisaeda H. et al.

WSX-1 15 required for resistance to Trypanosoma cruzi infection by regulation pro-inflammatory cytokine production.

WSX-1 15 通过调节促炎细胞因子的产生来抵抗克氏锥虫感染。

• 发表时间: 2003
• 期刊: Immunity 19・5
• 作者: Toyooka;K.;et al.;Kaneko O;Yano K;Kaneko 0;Yano K;Arakawa T;Sawasaki T;Arakawa T;Sawasaki T;Arakawa T;Kaneko O;Rungruang T;Sattabongkot J;Li F;Li F;Ling IT;Tsuboi T;Li F;Kongkasuriyachai D;Win TT;Duan X.et al.;Ishii K. et al.;Duan X.et al.;Ishii K. et al.;Duan X.et al.;Ishii K. et al.;Hisaeda H. et al.;Zhang M. et al.;Hisaeda H. et al.;Hisaeda H. et al.;Zhang M. et al.;Hisaeda H. et al.;Hisaeda H. et al.;Zhang M. et al.;Zhang M. et al.;Hisaeda H. et al.;Okamoto M. et al.;Obata C. et al.;Onishi K. et al.;Yamanaka A. et al.;Zhang M. et al.;Li Y.et al.;Hisaeda H. et al.;Okamoto M. et al.;Obata C. et al.;Onishi K. et al.;Yamanaka A. et al.;Zhang M. et al.;Li Y.et al.;Hisaeda H. et al.;Onishi K. et al.;Yamanaka A. et al.;Hamano S. et al.
• 通讯作者: Hamano S. et al.

Cathepsin L is crucial for Th1-type immune response during Leishmania major infection.

组织蛋白酶 L 对于利什曼原虫重大感染期间的 Th1 型免疫反应至关重要。

• 发表时间: 2004
• 期刊: Microbes and Infection Apr 6(5)
• 作者: Toyooka;K.;et al.;Kaneko O;Yano K;Kaneko 0;Yano K;Arakawa T;Sawasaki T;Arakawa T;Sawasaki T;Arakawa T;Kaneko O;Rungruang T;Sattabongkot J;Li F;Li F;Ling IT;Tsuboi T;Li F;Kongkasuriyachai D;Win TT;Duan X.et al.;Ishii K. et al.;Duan X.et al.;Ishii K. et al.;Duan X.et al.;Ishii K. et al.;Hisaeda H. et al.;Zhang M. et al.;Hisaeda H. et al.;Hisaeda H. et al.;Zhang M. et al.;Hisaeda H. et al.;Hisaeda H. et al.;Zhang M. et al.;Zhang M. et al.;Hisaeda H. et al.;Okamoto M. et al.;Obata C. et al.;Onishi K. et al.;Yamanaka A. et al.;Zhang M. et al.;Li Y.et al.;Hisaeda H. et al.;Okamoto M. et al.;Obata C. et al.;Onishi K. et al.
• 通讯作者: Onishi K. et al.