As a genetic adjuvant, CTA improves the immunogenicity of DNA vaccines in an ADP-ribosyltransferase activity- and IL-6-dependent manner.-猫眼课题宝

DOI：

10.1016/j.vaccine.2014.02.056

发表时间：

2014-04

期刊：

Vaccine

影响因子：

5.5

通讯作者：

中科院分区：

医学3区

文献类型：

作者：

Y. Wan;X. Ren;Y. Ren;Jing Wang;Zhidong Hu;Xiao-yan Xie;Jianqing Xu

霍乱毒素（CT）及其亚单位（A和B）作为蛋白疫苗的佐剂已被广泛研究。它们的潜在机制因所用接种途径而异。通过将CTA基因与HIV-1来源的Tat-Rev-Vif-Integrase-Nef融合基因或OVA基因融合，我们的研究表明，CTA在这些DNA疫苗中的融合在体外没有细胞毒性效应，并且显著提高了诱导的CD 8 +T细胞应答的数量和质量。进一步的实验表明，CTA在这些DNA疫苗中的融合以依赖于其ADP-核糖基转移酶活性的方式增加了IL-6的分泌，并且发现蛋白激酶A（PKA）是其下游信号传导的主要介体。通过ADP核糖基转移酶催化中心的定点突变和体内RNAi，我们证明了ADP核糖基转移酶活性和IL-6的上调是CTA基因介导的佐剂效应所必需的。这些发现表明，当与免疫原基因融合时，CTA基因可以作为一种有效的遗传佐剂，为CTA作为佐剂的机制提供了新的见解。

Cholera toxin (CT) and its subunits (A and B) have been intensively investigated as adjuvants for protein-based vaccines. Their underlying mechanisms vary with respect to the inoculation route used. By fusing the CTA gene to either the HIV-1-derived Tat-Rev-Vif-Integrase-Nef fusion gene or the OVA gene, our study showed that the fusion of CTA in these DNA vaccines had no cytotoxic effectin vitroand significantly improved both the quantity and quality of the elicited CD8+T cell responses. Further experiments identified that the fusion of CTA in these DNA vaccines augmented the secretion of IL-6 in a manner that was dependent on its ADP-ribosyltransferase activity, and protein kinase A (PKA) was found to be the major mediator of its downstream signaling. By site-directed mutagenesis of the ADP-ribosyltransferase catalytic center andin vivoRNAi, we demonstrated that the ADP-ribosyltransferase activity and the upregulation of IL-6 were required for the CTA gene-mediated adjuvant effect. These findings demonstrate that when fused to an immunogen gene, the CTA gene could serve as a potent genetic adjuvant, providing new insights into the mechanisms of CTA as an adjuvant.

As a genetic adjuvant, CTA improves the immunogenicity of DNA vaccines in an ADP-ribosyltransferase activity- and IL-6-dependent manner.

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