Toxicity and immunogenicity of Enterotoxigenic Escherichia coli heat-labile and heat-stable toxoid fusion 3xSTa(A14Q)-LT(S63K/R192G/L211A) in a murine model.
Toxicity and immunogenicity of Enterotoxigenic Escherichia coli heat-labile and heat-stable toxoid fusion 3xSTa(A14Q)-LT(S63K/R192G/L211A) in a murine model.
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DOI：
10.1371/journal.pone.0077386
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
STa Toxoid Vaccine Consortium Group
中科院分区：
文献类型：
--
作者：
Zhang C;Knudsen DE;Liu M;Robertson DC;Zhang W;STa Toxoid Vaccine Consortium Group
腹泻是幼儿死亡的第二大原因。产肠毒素大肠杆菌（ETEC）是引起腹泻的最常见细菌。粘附素和肠毒素是ETEC腹泻的毒力决定因素。粘附素介导细菌附着和定植，肠毒素包括热不稳定（LT）和热稳定Ib型毒素（STa）破坏宿主细胞中的流体稳态，导致流体分泌过多和腹泻。因此，粘附素和肠毒素是ETEC疫苗开发的主要目标。最近的一项研究报道了在LTR 192 G的N-或C-末端或A亚基内部融合的具有STa类毒素（STaP 13 F）的类毒素融合物引发中和抗毒素抗体，并提出了类毒素融合物在ETEC疫苗开发中的应用（Liu等人，Infect. Immun. 79：4002-4009，2011）。在这项研究中，我们产生了一种不同的STa类毒素（STaA 14 Q）和一种三突变LT类毒素（LTS 63 K/R192 G/L211 A，tmLT），构建了一种携带3个STaA 14 Q拷贝的类毒素融合体（3xSTaA 14 Q-tmLT），以进一步促进抗STa免疫原性，并在小鼠模型中评估了抗原安全性和免疫原性，以探索其用于ETEC疫苗开发的潜力。用这种融合抗原免疫的小鼠没有显示出不良反应，并且产生了抗毒素抗体，特别是通过IP途径。检测到抗LT抗体，并显示体外中和CT。在免疫小鼠中也检测到抗STa抗体，并且来自IP免疫小鼠的血清在体外中和STa毒素。本研究的数据表明，类毒素融合蛋白3xSTaA 14 Q-tmLT是安全的，并且可以诱导中和抗毒素抗体，为ETEC腹泻疫苗的开发提供了有用的信息。
Diarrhea is the second leading cause of death to young children. Enterotoxigenic Escherichia coli (ETEC) are the most common bacteria causing diarrhea. Adhesins and enterotoxins are the virulence determinants in ETEC diarrhea. Adhesins mediate bacterial attachment and colonization, and enterotoxins including heat-labile (LT) and heat-stable type Ib toxin (STa) disrupt fluid homeostasis in host cells that leads to fluid hyper-secretion and diarrhea. Thus, adhesins and enterotoxins have been primarily targeted in ETEC vaccine development. A recent study reported toxoid fusions with STa toxoid (STaP13F) fused at the N- or C-terminus, or inside the A subunit of LTR192G elicited neutralizing antitoxin antibodies, and suggested application of toxoid fusions in ETEC vaccine development (Liu et al., Infect. Immun. 79:4002-4009, 2011). In this study, we generated a different STa toxoid (STaA14Q) and a triple-mutant LT toxoid (LTS63K/R192G/L211A, tmLT), constructed a toxoid fusion (3xSTaA14Q-tmLT) that carried 3 copies of STaA14Q for further facilitation of anti-STa immunogenicity, and assessed antigen safety and immunogenicity in a murine model to explore its potential for ETEC vaccine development. Mice immunized with this fusion antigen showed no adverse effects, and developed antitoxin antibodies particularly through the IP route. Anti-LT antibodies were detected and were shown neutralizing against CT in vitro. Anti-STa antibodies were also detected in the immunized mice, and serum from the IP immunized mice neutralized STa toxin in vitro. Data from this study indicated that toxoid fusion 3xSTaA14Q-tmLT is safe and can induce neutralizing antitoxin antibodies, and provided helpful information for vaccine development against ETEC diarrhea.
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影响因子：
4.2
作者：
Liu M;Zhang C;Mateo K;Nataro JP;Robertson DC;Zhang W
通讯作者：
Zhang W
影响因子：
--
作者：
Ruan, Xiaosai;Liu, Mei;Zhang, Weiping
通讯作者：
Zhang, Weiping
影响因子：
3.1
作者：
CLEMENTS, JD
通讯作者：
CLEMENTS, JD
影响因子：
15.9
作者：
Gaastra, W;Svennerholm, AM
通讯作者：
Svennerholm, AM
影响因子：
3.7
作者：
Jackson, Erin M.;Herbst-Kralovetz, Melissa M.
通讯作者：
Herbst-Kralovetz, Melissa M.