Modified heat-stable toxins (hSTa) of enterotoxigenic Escherichia coli lose toxicity but display antigenicity after being genetically fused to heat-labile toxoid LT(R192G).
Modified heat-stable toxins (hSTa) of enterotoxigenic Escherichia coli lose toxicity but display antigenicity after being genetically fused to heat-labile toxoid LT(R192G).
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作者：
Liu M;Zhang C;Mateo K;Nataro JP;Robertson DC;Zhang W
产肠毒素大肠杆菌（ETEC）菌株是人类和动物腹泻的主要原因。ETEC产生的热稳定（STa）和热不稳定（LT）肠毒素破坏宿主小肠上皮细胞的液体稳态，引起液体和电解质分泌过多，导致腹泻。产生STa或LT的ETEC菌株毒性足以引起腹泻，因此ETEC疫苗中必须包含STa和LT抗原。然而，（STa的）强毒性和差免疫原性阻止它们直接用作疫苗组分。虽然LT类毒素，尤其是LT（R192 G）被用于疫苗开发，但STa类毒素尚未被包括在内。最近的一项研究（IAI，78：316-325）证明，猪型STa类毒素[pSTa（P12 F）和pSTa（A13 Q）]在与猪型LT类毒素[pLT（R192 G）]融合后引发保护性抗STa抗体。在这项研究中，我们取代了第8，第9，第16，或第17位氨基酸的人型STa（hSTa），并产生28个修饰的STa肽。我们测试了每种STa肽的毒性和结构完整性，发现几乎所有修饰的STa蛋白都显示出结构改变和毒性降低。基于结构相似性和毒性活性，选择三种修饰的STa肽：STa（E8 A）、STa（T16 Q）和STa（G17 S）来构建LT 192-STa-类毒素融合物。构建的融合体用于免疫小鼠，并且免疫的小鼠产生抗STa抗体。本研究的结果为开发针对ETEC腹泻的类毒素疫苗提供了有用的信息。
Enterotoxigenic Escherichia coli (ETEC) strains are a major cause of diarrhea in humans and animals. Heat-stable (STa) and heat-labile (LT) enterotoxins produced by ETEC disrupt fluid homeostasis in host small intestinal epithelial cells and cause fluid and electrolyte hyper-secretion that leads to diarrhea. ETEC strains producing STa or LT are sufficiently virulent to cause diarrhea, therefore STa and LT antigens must be included in ETEC vaccines. However, potent toxicity and poor immunogenicity (of STa) prevent them from being directly applied as vaccine components. While LT toxoids, especially LT(R192G), being used in vaccine development, STa toxoids have not been included. A recent study (IAI, 78:316-325) demonstrated porcine-type STa toxoids [pSTa(P12F) and pSTa(A13Q)] elicited protective anti-STa antibodies after being fused to a porcine-type LT toxoid [pLT(R192G)]. In this study, we substituted the 8th, 9th, 16th, or the 17th amino acid of a human-type STa (hSTa) and generated 28 modified STa peptides. We tested each STa peptide for toxicity and structure integrity, and found nearly all modified STa proteins showed structure alteration and toxicity reduction. Based on structure similarity and toxic activity, three modified STa peptides: STa(E8A), STa(T16Q) and STa(G17S), were selected to construct LT192-STa-toxoid fusions. Constructed fusions were used to immunize mice, and immunized mice developed anti-STa antibodies. Results from this study provide useful information in developing toxoid vaccines against ETEC diarrhea.
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