Comparison of different live vaccine strategies in vivo for delivery of protein antigen or antigen-encoding DNA and mRNA by virulence-attenuate Listeria monocytogenes
Comparison of different live vaccine strategies in vivo for delivery of protein antigen or antigen-encoding DNA and mRNA by virulence-attenuate Listeria monocytogenes
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DOI：
10.1128/iai.00112-06
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发表时间：
2006-07-01
影响因子：
3.1
通讯作者：
Pilgrim, Sabine
中科院分区：
文献类型：
--
作者：
Loeffler, Daniela I. M.;Schoen, Christoph U.;Pilgrim, Sabine
由于单核细胞增生李斯特菌的细胞内生活方式，其可用于将蛋白质抗原或编码此类抗原的DNA和mRNA直接递送到宿主细胞的胞质溶胶中。在这项研究中，我们比较了抗原特异性的CD 8和CD 4 T细胞的体内激活效率时，分泌的抗原是由L。单核细胞增多症或当抗原编码质粒DNA或mRNA被L.单核细胞增多症。用自毁L.单核细胞增多症载体递送编码非分泌形式的卵清蛋白（OVA）的mRNA导致显著的OVA特异性CD 8 T细胞应答。而L.递送OVA编码DNA的单核细胞增多症未能产生特异性T细胞。通过载体细菌分泌OVA产生涉及OVA特异性CD 8和CD 4 T细胞的最强免疫应答。此外，我们研究了一种自毁的、毒力减弱的L.单核细胞增多症aroA/B突变体。与野生型菌株相比，当使用高剂量（静脉内给予每只动物5 × 10（7）CFU）时，该突变体仅表现出轻微的肝毒性，并且它还能够将足量的分泌型OVA输送到小鼠体内。因此，本文的研究结果可为L.在新的疫苗接种策略中，单核细胞增多症作为用于递送蛋白质和核酸疫苗的减毒载体。
Listeria monocytogenes can be used to deliver protein antigens or DNA and mRNA encoding such antigens directly into the cytosol of host cells because of its intracellular lifestyle. In this study, we compare the in vivo efficiencies of activation of antigen-specific CD8 and CD4 T cells when the antigen is secreted by L. monocytogenes or when antigen-encoding plasmid DNA or mRNA is released by self-destructing strains of L. monocytogenes. Infection of mice with self-destructing L. monocytogenes carriers delivering mRNA that encodes a nonsecreted form of ovalbumin (OVA) resulted in a significant OVA-specific CD8 T-cell response. In contrast, infection with L. monocytogenes delivering OVA-encoding DNA failed to generate specific T cells. Secretion of OVA by the carrier bacteria yielded the strongest immune response involving OVA-specific CD8 and CD4 T cells. In addition, we investigated the antigen delivery capacity of a self-destructing, virulence-attenuated L. monocytogenes aroA/B mutant. In contrast to the wild-type strain, this mutant exhibited only marginal liver toxicity when high doses (5 X 10(7) CFU per animal administered intravenously) were used, and it was also able to deliver sufficient amounts of secreted OVA into mice. Therefore, the results presented here could lay the groundwork for a rational combination of L. monocytogenes as an attenuated carrier for the delivery of protein and nucleic acid vaccines in novel vaccination strategies.