In Vivo Synthesis of Cyclic-di-GMP Using a Recombinant Adenovirus Preferentially Improves Adaptive Immune Responses against Extracellular Antigens.
In Vivo Synthesis of Cyclic-di-GMP Using a Recombinant Adenovirus Preferentially Improves Adaptive Immune Responses against Extracellular Antigens.
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DOI：
10.4049/jimmunol.1501272
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发表时间：
2016-02-15
期刊：
影响因子：
--
通讯作者：
Amalfitano A
中科院分区：
文献类型：
--
作者：
Alyaqoub FS;Aldhamen YA;Koestler BJ;Bruger EL;Seregin SS;Pereira-Hicks C;Godbehere S;Waters CM;Amalfitano A
迫切需要更有效的疫苗佐剂来增强抗原特异性适应性免疫应答的诱导。最近的报告表明，细菌第二信使双-(3′–5′)-环二聚鸟苷单磷酸 (c-di-GMP) 充当先天免疫系统调节剂。我们最近将霍乱弧菌二鸟苷酸环化酶 (DGC) 纳入腺病毒 (Ad) 疫苗中，促进 c-di-GMP 的产生以及小鼠的促炎反应。在这里，我们将更有效的 DGC VCA0848 重组为非复制腺病毒血清型 5 (AdVCA0848)，当在哺乳动物细胞体内表达时，它会产生大量的 c-di-GMP。与对照载体相比，该新平台进一步改善了对小鼠给药后早期 I 型干扰素 β (IFN-β) 的诱导以及先天性和适应性免疫细胞的激活。通过 IFN-γ 和 IL-2 ELISPOT 检测，细胞外蛋白卵清蛋白 (OVA) 和 AdVCA0848 佐剂的共同给药显着改善了 OVA 特异性 T 细胞反应，同时还改善了 OVA 特异性体液 B 细胞适应性反应。此外，我们发现 AdVCA0848 与另一种表达 HIV-1 衍生抗原 Gag (AdGag) 或艰难梭菌衍生毒素 B (AdToxB) 的 Ad5 载体共同给药，对 Gag 和 ToxB 特异性适应性免疫反应的诱导产生显着的抑制作用。作为原理证明，这些数据证实，c-di-GMP 的体内合成可刺激强烈的先天免疫反应，该反应与增强的对同时施用的细胞外抗原的适应性免疫反应相关，细胞外抗原可用作佐剂，增强基于蛋白质的疫苗平台针对微生物感染和癌症的有效免疫反应。
There is a compelling need for more effective vaccine adjuvants to augment induction of antigen specific adaptive immune responses. Recent reports suggested the bacterial second messenger bis-(3′–5′)-cyclic-dimeric-guanosine monophosphate (c-di-GMP) acts as an innate immune system modulator. We recently incorporated a Vibrio cholerae diguanylate cyclase (DGC) into an adenovirus (Ad) vaccine, fostering production of c-di-GMP as well as pro-inflammatory responses in mice. Here, we recombined a more potent DGC, VCA0848, into a non-replicating adenovirus serotype 5 (AdVCA0848) that produces elevated amounts of c-di-GMP when expressed in mammalian cells in vivo. This novel platform further improved induction of type I interferon β (IFN-β) and activation of innate and adaptive immune cells early after administration into mice as compared to control vectors. Co-administration of the extracellular protein ovalbumin (OVA) and the AdVCA0848 adjuvant significantly improved OVA-specific T cell responses as detected by IFN-γ and IL-2 ELISPOT, while also improving OVA-specific humoral B cell adaptive responses. Additionally, we found that co-administration of AdVCA0848 with another Ad5 vector expressing the HIV-1 derived antigen Gag (AdGag) or the Clostridium difficile-derived Toxin B (AdToxB), resulted in significant inhibitory effects on the induction of Gag and ToxB-specific adaptive immune responses. As a proof of principle, these data confirm that in vivo synthesis of c-di-GMP stimulates strong innate immune responses that correlate with enhanced adaptive immune responses to concomitantly administered extracellular antigen, which can be utilized as an adjuvant to heighten effective immune responses for protein-based vaccine platforms against microbial infections and cancers.
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影响因子：
4.4
作者：
Aldhamen, Yasser Ali;Seregin, Sergey S.;Amalfitano, Andrea
通讯作者：
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