Efficacy of EHEC gold nanoparticle vaccines evaluated with the Shiga toxin-producing Citrobacter rodentium mouse model.
Efficacy of EHEC gold nanoparticle vaccines evaluated with the Shiga toxin-producing Citrobacter rodentium mouse model.
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DOI：
10.1128/spectrum.02261-23
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发表时间：
2024-01-11
影响因子：
3.7
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中科院分区：
文献类型：
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肠出血性大肠埃希菌(EHEC)是引起人类腹泻疾病食源性暴发的一组病原菌。虽然EHEC是发病率的主要原因以及与志贺毒素(STX)的产生有关的溶血性尿毒症综合征，但目前还没有批准用于人类的疫苗。全面评估疫苗对EHEC感染的效力是具有挑战性的，因为传统的成年小鼠对EHEC感染具有固有的抵抗力，不会出现这种疾病的显著症状。因此，在这项研究中，我们利用一种已经裂解的小鼠病原体轮状柠檬酸杆菌菌株来产生Stx2d，该菌株在口服攻击后持续导致致命感染和其他可测量的疾病后果，以进一步评估我们以前配方的EHEC金纳米颗粒(AuNP)疫苗的保护效果。使用这个模型，以及一个不产生Stx2d的轮状芽孢杆菌菌株，我们评估了AuNPs与三种EHEC抗原结合的保护作用：ESCC，LomW和Intiin(Eae)。我们证明，用AuNP-EAE鼻腔免疫小鼠可以部分保护小鼠免受产生Stx2d的轮状芽孢杆菌引起的死亡，并且与仅使用佐剂治疗的小鼠相比，AuNP-ESCC和AuNP-Eae适度地减轻了不产生Stx2d的轮状芽孢杆菌菌株的肠道负担。此外，AuNP蛋白疫苗诱导抗原和病原体特异性的血清免疫球蛋白G和粪便免疫球蛋白A对抗肠出血性肠炎和轮齿弧菌，而体外功能分析表明，所激发的抗体具有杀菌作用，并阻止轮齿弧菌与肠上皮细胞的黏附。我们认为，轮齿毛虫小鼠的数据可以转化为保护相关因素。肠出血性大肠杆菌(EHEC)仍然是世界范围内腹泻疾病和并发症的重要原因，特别是在儿童中，但目前还没有可供人类使用的疫苗。由于动物模型不一致而导致的临床前评估不足，仍然是新疫苗开发的主要障碍。我们证明了产生Stx2d的轮状柠檬酸杆菌在评估疫苗有效性方面的有效性，因为它更接近于概括由EHEC引起的人类疾病。
Enterohemorrhagic Escherichia coli (EHEC) is a group of pathogenic bacteria responsible for several foodborne-associated outbreaks of human diarrheal disease. Although EHEC is a major cause of morbidity as well as the condition known as hemolytic uremic syndrome, linked to the production of Shiga toxins (Stx), there are no licensed vaccines approved for human use. Fully assessing vaccine efficacy against EHEC infections is challenging because conventional adult mice are inherently resistant to EHEC infection and do not develop hallmark symptoms of the disease. Therefore, in this study, we utilized a strain of the murine pathogen Citrobacter rodentium that has been lysogenized to produce Stx2d, which consistently causes lethal infection and other measurable disease outcomes following oral challenge, to further evaluate the protective efficacy of our previously formulated EHEC gold nanoparticle (AuNP) vaccines. Using this model, along with a non-Stx2d-producing C. rodentium strain, we assessed the protection conferred by AuNPs conjugated to three EHEC antigens: EscC, LomW, and intimin (Eae). We demonstrated that intranasally immunizing mice with AuNP-Eae provides partial protection against mortality caused by Stx2d-producing C. rodentium and that AuNP-EscC and AuNP-Eae moderately reduce intestinal burden of the non-Stx2d-producing C. rodentium strain compared with adjuvant-only-treated mice. Additionally, the AuNP-protein vaccines induced antigen- and pathogen-specific serum IgG and fecal IgA against both EHEC and C. rodentium while in vitro functional assays indicate that the elicited antibodies are bactericidal and prevent adherence of C. rodentium to intestinal epithelial cells. We propose that C. rodentium murine data could translate into correlates of protection. Enterohemorrhagic Escherichia coli (EHEC) remains an important cause of diarrheal disease and complications worldwide, especially in children, yet there are no available vaccines for human use. Inadequate pre-clinical evaluation due to inconsistent animal models remains a major barrier to novel vaccine development. We demonstrate the usefulness of Stx2d-producing Citrobacter rodentium in assessing vaccine effectiveness because it more closely recapitulates human disease caused by EHEC.
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影响因子：
3.1
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