Polyvalent Protein Adhesin MEFA-II Induces Functional Antibodies against Enterotoxigenic Escherichia coli (ETEC) Adhesins CS7, CS12, CS14, CS17, and CS21 and Heat-Stable Toxin (STa).
Polyvalent Protein Adhesin MEFA-II Induces Functional Antibodies against Enterotoxigenic Escherichia coli (ETEC) Adhesins CS7, CS12, CS14, CS17, and CS21 and Heat-Stable Toxin (STa).
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多价蛋白粘附素 MEFA-II 诱导产生针对产肠毒素大肠杆菌 (ETEC) 粘附素 CS7、CS12、CS14、CS17 和 CS21 以及热稳定毒素 (STa) 的功能性抗体。
DOI：
10.1128/aem.00683-23
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发表时间：
2023
影响因子：
4.4
通讯作者：
Zhang,Weiping
中科院分区：
文献类型：
--
作者：
Upadhyay,Ipshita;Parvej,ShafiullahMD;Li,Siqi;Lauder,KathrynL;Shen,Yiyang;Zhang,Weiping
产肠毒素大肠杆菌 (ETEC) 是儿童腹泻和旅行者腹泻的常见原因，目前尚无获得许可的疫苗。 ETEC 菌株产生肠毒素（不耐热毒素，LT；热稳定性毒素，STa）和粘附素 CFA/I、CFA/II（CS1-CS3）或 CFA/IV（CS4-CS6），这归因于大多数 ETEC 相关腹泻病例，因此这两种毒素（STa、LT）和七种粘附素（CFA/I、CS1 至 CS6）历来是 ETEC 疫苗的主要目标发展。然而，最近的研究表明，含有粘附素 CS14、CS21、CS7、CS17 和 CS12 的 ETEC 菌株也很常见，并会导致中度至重度腹泻；这些粘附素现在也被认为是 ETEC 疫苗的抗原靶标。在这项研究中，我们应用了基于表位和结构的多表位融合抗原（MEFA）疫苗学平台，并构建了一种多价蛋白来呈现这五种粘附素（也是一种 STa 类毒素）的免疫显性连续 B 细胞表位；然后，我们表征了这种蛋白质抗原（称为粘附素 MEFA-II）的广泛免疫原性，并评估了针对每种靶向粘附素和 STa 毒素的抗体功能。数据显示，用粘附素 MEFA-II 蛋白进行肌肉注射免疫的小鼠产生了针对目标粘附素和毒素 STa 的强效 IgG。重要的是，抗原衍生抗体显着抑制表达粘附素 CS7、CS12、CS14、CS17 或 CS21 的 ETEC 细菌的粘附，并降低 STa 肠毒性。这些结果表明粘附素 MEFA-II 蛋白具有广泛的免疫原性并诱导交叉功能抗体，表明粘附素 MEFA-II 可以成为有效的 ETEC 疫苗抗原；如果将粘附素 MEFA-II 纳入 ETEC 候选疫苗中，则可以扩大疫苗覆盖范围并提高针对 ETEC 相关儿童腹泻和旅行者腹泻的功效。 重要性 ETEC 是儿童腹泻和旅行者腹泻的主要原因，对全球健康构成威胁，目前缺乏针对 ETEC 的有效疫苗。 ETEC 疫苗开发的关键挑战是 ETEC 细菌表达异质毒力决定簇（>25 种粘附素和两种毒素）。虽然目前针对七种最流行的 ETEC 粘附素（CFA/I、CS1 至 CS6）的策略可能会导致针对许多临床病例的疫苗的出现，但 ETEC 菌株的流行率会随着时间和地理位置的变化而发生长期变化，并且表达其他粘附素（主要是 CS7、CS12、CS14、CS17 和 CS21）的 ETEC 也会引起中度至重度腹泻。然而，在传统方法下不可能开发出针对多达 12 种粘附素的 ETEC 疫苗。这项研究使用独特的疫苗学平台来创建多价抗原，并证明了该抗原针对目标 ETEC 粘附素的广泛免疫原性和功能，从而能够开发出基本上针对所有重要 ETEC 菌株的广泛保护性疫苗。
There are no licensed vaccines for enterotoxigenic Escherichia coli (ETEC), a common cause of children’s diarrhea and travelers’ diarrhea. ETEC strains producing enterotoxins (heat-labile toxin, LT; heat-stable toxin, STa) and adhesins CFA/I, CFA/II (CS1-CS3) or CFA/IV (CS4-CS6) attributed to a majority of ETEC-associated diarrheal cases, thus the two toxins (STa, LT) and the seven adhesins (CFA/I, CS1 to CS6) are historically the primary targets in ETEC vaccine development. Recent studies, however, revealed that ETEC strains with adhesins CS14, CS21, CS7, CS17, and CS12 are also prevalent and cause moderate-to-severe diarrhea; these adhesins are now considered antigen targets as well for ETEC vaccines. In this study, we applied the epitope- and structure-based multiepitope-fusion-antigen (MEFA) vaccinology platform and constructed a polyvalent protein to present immuno-dominant continuous B-cell epitopes of these five adhesins (also an STa toxoid); we then characterized this protein antigen’s (termed as adhesin MEFA-II) broad immunogenicity and evaluated antibody functions against each targeted adhesin and STa toxin. Data showed that mice intramuscularly immunized with adhesin MEFA-II protein developed robust IgG to the targeted adhesins and toxin STa. Importantly, the antigen-derived antibodies significantly inhibited adherence of ETEC bacteria expressing adhesin CS7, CS12, CS14, CS17, or CS21 and reduced STa enterotoxicity. These results indicated that adhesin MEFA-II protein is broadly immunogenic and induces cross-functional antibodies, suggesting adhesin MEFA-II can be an effective ETEC vaccine antigen; if included in an ETEC vaccine candidate, adhesin MEFA-II can expand vaccine coverage and increase efficacy against ETEC-associated children’s diarrhea and travelers’ diarrhea.IMPORTANCEAn effective vaccine is lacking against ETEC, a primary cause of children’s diarrhea and traveler’s diarrhea and a threat to global health. The key challenge in ETEC vaccine development is that ETEC bacteria express heterogeneous virulence determinants (>25 adhesins and two toxins). While the current strategy to target the seven most prevalent ETEC adhesins (CFA/I, CS1 to CS6) potentially lead to a vaccine against many clinical cases, the prevalence of ETEC strains shifts chronically and geographically, and ETEC expressing other adhesins, mainly CS7, CS12, CS14, CS17, and CS21, also cause moderate-to-severe diarrhea. However, it is impossible to develop an ETEC vaccine to target as many as 12 adhesins under conventional approaches. This study used a unique vaccinology platform to create a polyvalent antigen and demonstrated the antigen's broad immunogenicity and functions against the targeted ETEC adhesins, enabling the development of a broadly protective vaccine essentially against all of the important ETEC strains.