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首页> 外文期刊>Infection and immunity >Differential Biological and Adjuvant Activities of Cholera Toxin and Escherichia coli Heat-Labile Enterotoxin Hybrids
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Differential Biological and Adjuvant Activities of Cholera Toxin and Escherichia coli Heat-Labile Enterotoxin Hybrids

机译：霍乱毒素和大肠杆菌热不稳定肠毒素杂种的差异生物学和佐剂活性

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Two bacterial products that have been demonstrated to function as mucosal adjuvants are cholera toxin (CT), produced by various strains of Vibrio cholerae, and the heat-labile enterotoxin (LT) produced by some enterotoxigenic strains of Escherichia coli. Although LT and CT have many features in common, they are clearly distinct molecules with biochemical and immunologic differences which make them unique. The goal of this study was to determine the basis for these biological differences by constructing and characterizing chimeric CT-LT molecules. Toxin gene fragments were subcloned to create two constructs, each expressing the enzymatically active A subunit of one toxin and the receptor binding B subunit of the other toxin. These hybrid toxins were purified, and the composition and assembly of CT A subunit (CT-A)-LT B subunit (LT-B) and LT A subunit (LT-A)-CT B subunit (CT-B) were confirmed. Hybrids were evaluated for enzymatic activity, as measured by the accumulation of cyclic AMP in Caco-2 cells, and the enterotoxicity of each toxin was assessed in a patent-mouse assay. The results demonstrated that LT-A–CT-B induces the accumulation of lower levels of cyclic AMP and has less enterotoxicity than either wild-type toxin or the other hybrid. Nonetheless, this hybrid retains adjuvant activity equivalent to or greater than that of either wild-type toxin or the other hybrid when used in conjunction with tetanus toxoid for intranasal immunization of BALB/c mice. Importantly, the ability of LT to induce a type 1 cytokine response was found to be a function of LT-A. Specifically, LT-A–CT-B was able to augment the levels of antigen-specific gamma interferon (IFN-γ) and interleukin 5 to levels comparable to those achieved with native LT, while CT-A–LT-B and native CT both produced lower levels of antigen-specific IFN-γ. Thus, these toxin hybrids possess unique biological characteristics and provide information about the basis for differences in the biological activities observed for CT and LT.
机译：两种被证明可作为粘膜佐剂的细菌产品分别是霍乱弧菌的各种菌株产生的霍乱毒素（CT）和某些肠毒素的肠毒素产生的热不稳定肠毒素（LT）。大肠埃希菌。尽管LT和CT具有许多共同点，但它们显然是具有生化和免疫学差异的截然不同的分子，这使其与众不同。这项研究的目的是通过构建和表征嵌合CT-LT分子来确定这些生物学差异的基础。将毒素基因片段亚克隆以创建两个构建体，每个构建体表达一种毒素的酶活性A亚基和另一种毒素的受体结合B亚基。纯化这些杂合毒素，并确认CT A亚基（CT-A）-LT B亚基（LT-B）和LT A亚基（LT-A）-CT B亚基（CT-B）的组成和组装。通过在Caco-2细胞中环AMP的积累来评估杂合体的酶促活性，并通过专利-小鼠试验评估每种毒素的肠毒性。结果表明，与野生型毒素或其他杂种相比，LT-A–CT-B诱导了较低水平的环状AMP的积累，并具有较低的肠毒性。然而，当与破伤风类毒素一起用于鼻内免疫BALB / c小鼠时，该杂种保留的佐剂活性等于或大于野生型毒素或其他杂种的佐剂活性。重要的是，发现LT诱导1型细胞因子应答的能力是LT-A的功能。具体而言，LT-A–CT-B能够将抗原特异性γ干扰素（IFN-γ）和白介素5的水平提高到与天然LT相当的水平，而CT-A–LT-B和天然CT两者均产生较低水平的抗原特异性IFN-γ。因此，这些毒素杂种具有独特的生物学特性，并提供了有关CT和LT观察到的生物学活性差异基础的信息。

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