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首页> 外文期刊>Infection and immunity >Pathogenicity and Immunogenicity of a Vaccine Strain of Listeria monocytogenes That Relies on a Suicide Plasmid To Supply an Essential Gene Product
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Pathogenicity and Immunogenicity of a Vaccine Strain of Listeria monocytogenes That Relies on a Suicide Plasmid To Supply an Essential Gene Product

机译：依靠自杀质粒提供必需基因产物的单核细胞增生李斯特菌疫苗株的致病性和免疫原性

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Listeria monocytogenes is a bacterial pathogen that elicits a strong cellular immune response and thus has potential use as a vaccine vector. An attenuated strain, L. monocytogenes dal dat, produced by deletion of two genes (dal and dat) used for d-alanine synthesis, induces cytotoxic T lymphocytes and protective immunity in mice following infection in the presence of d-alanine. In order to obviate the dependence of L. monocytogenes dal dat on supplemental d-alanine yet retain its attenuation and immunogenicity, we explored mechanisms to allow transient endogenous synthesis of the amino acid. Here, we report on a derivative strain, L. monocytogenes dal dat/pRRR, that expresses a dal gene and synthesizes d-alanine under highly selective conditions. We constructed the suicide plasmid pRRR carrying a dal gene surrounded by two res1 sites and a resolvase gene, tnpR, which acts at the res1 sites. The resolvase gene is regulated by a promoter activated upon exposure to host cell cytosol. L. monocytogenes dal dat/pRRR was thus able to grow in liquid culture and to infect host cells without d-alanine supplementation. However, after infection of these cells, resolvase-mediated excision of the dal gene resulted in strong down-regulation of racemase expression. As a result, this system allowed only transient growth of L. monocytogenes dal dat/pRRR in infected cells and survival in animals for only 2 to 3 days. Nevertheless, mice immunized with L. monocytogenes dal dat/pRRR generated listeriolysin O-specific effector and memory CD8+ T cells and were protected against lethal challenge by wild-type Listeria. This vector may be an attractive vaccine candidate for the induction of protective cellular immune responses.
机译：单核细胞增生性李斯特菌是一种细菌病原体，可引起强烈的细胞免疫反应，因此有可能用作疫苗载体。减毒株 L。 d-丙氨酸合成所用的两个基因（ dal 和 dat ）缺失产生的单核细胞增生因子dal dat 可诱导小鼠的细胞毒性T淋巴细胞和保护性免疫d-丙氨酸存在下感染。为了消除对 L的依赖性。补充d-丙氨酸中的单核细胞增生因子dal dat 仍保留其减毒和免疫原性，我们探索了允许氨基酸瞬时内源合成的机制。在这里，我们报道了一个衍生菌株， L。单核细胞基因dal dat / pRRR，可表达 dal 基因并在高度选择性的条件下合成d-丙氨酸。我们构建了一个自杀质粒pRRR，该质粒带有一个被两个 res1 位点包围的 dal 基因和一个在上起作用的分辨酶基因 tnpR 。 res1 网站。 Resolvase基因受暴露于宿主细胞胞质溶胶后激活的启动子调控。 L。因此，单核细胞增生因子dal dat / pRRR能够在液体培养物中生长并感染宿主细胞而无需添加d-丙氨酸。但是，感染这些细胞后，由解析酶介导的 dal 基因切除导致消旋酶表达的强烈下调。结果，该系统仅允许 L的瞬时生长。单核细胞增生病dal dat / pRRR在受感染的细胞中的存活率以及在动物中的存活期只有2-3天。然而，用 L免疫的小鼠。单核细胞增生因子dal dat / pRRR产生了李斯特菌溶血素O特异性效应子和记忆CD8 + T细胞，并受到野生型 Listeria 的致命攻击。该载体可以是诱导保护性细胞免疫应答的有吸引力的疫苗候选物。

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