Developing effective nanovaccines against pathogenic Escherichia coli

摘要 我们对致病性大肠杆菌研究领域的科学贡献是加速了 使用新的抗原和肠道感染的小鼠模型开发有效的疫苗， 不仅能预防肠出血性大肠杆菌。大肠杆菌（EHEC）O 157：H7，但也防止其他 致病性大肠大肠杆菌感染。因此，我们研究的长远目标是为人类的进化提供新的理论基础 关于致病性E.大肠杆菌定植，同时阐明保护性免疫反应， 将其纳入疫苗的开发中。我们建议的中心假设是， 与纳米疫苗偶联将具有免疫原性，保护性抗体的刺激将破坏定植 不同致病性E.大肠杆菌菌株。这一假设是基于强有力的实验前提 这表明，金纳米粒子耦合到表面暴露的EHEC抗原（由我们的生物- 免疫信息学方法）引起与肠道免疫应答减少相关的宿主免疫应答。 肠出血性大肠杆菌O 157：H7定植。近年来的研究表明，将抗原偶联到金载体上， 纳米颗粒显著增强了对EHEC O 157：H7感染的保护性免疫， 接种疫苗的小鼠降低肠致病性E. coliO 127：H6和肠聚集性E. coli O104：H4。我们提出的实验方法将集中在两个可重复的和科学合理的 目标：优化含有预防肠出血性大肠杆菌感染的抗原的金纳米颗粒疫苗（目标1）， 阐明防止定植所需的免疫应答，并测试针对 其他致病性E.大肠杆菌菌株（Aim 2）。这项工作意义重大，因为它有望提供进步 在开发一种完全保护性的金纳米颗粒疫苗，防止由EHEC引起的感染， O 157：H7，并且这样的疫苗也将有效地针对其他致病性E.大肠杆菌菌株，无 影响了E.大肠菌群这项研究将阐明毒力的共同联系， 这些细菌病原体的机制，然后可以用于致病性E.大肠杆菌 特异性粘膜疫苗。

Abstract Our scientific contribution to the field of pathogenic Escherichia coli research has been to accelerate the development of an effective vaccine, using novel antigens and murine models of intestinal infection, that can not only protect against enterohemorrhagic E. coli (EHEC) O157:H7 but also prevent colonization of other pathogenic E. coli infections. Therefore, the long-term goal of our study is to provide new fundamental knowledge regarding pathogenic E. coli colonization, while elucidating protective immune responses that can be incorporated in the development of a vaccine. The central hypothesis of our proposal is that novel antigens coupled to nanovaccines will be immunogenic, and stimulation of protective antibodies will disrupt colonization by different pathogenic E. coli strains. This hypothesis is based on the strong experimental premise demonstrating that gold nanoparticles coupled to surface-exposed EHEC antigens (defined by our bio- immunoinformatic approach) elicited host immune responses that correlate with reduction in the intestinal colonization by EHEC O157:H7. Our progress in recent years demonstrated that coupling antigens to gold nanoparticles significantly enhances protective immunity against EHEC O157:H7 infection, and the serum from vaccinated mice reduces adherence/virulence of enteropathogenic E. coli O127:H6 and enteroaggregative E. coli O104:H4. Our proposed experimental approach will focus on two reproducible and scientifically sound aims: Optimize a gold nanoparticle vaccine containing antigens that prevent EHEC infections (Aim 1), and elucidate the immune responses required to prevent colonization and test cross-protective properties against other pathogenic E. coli strains (Aim 2). This work is significant because it is expected to provide advancement in the development of a fully protective gold nanoparticle vaccine that prevents infections caused by EHEC O157:H7, and such a vaccine will also be effective at targeting other pathogenic E. coli strains, without affecting the commensal E. coli microbiota. This study will elucidate the common links in the virulence mechanisms of these bacterial pathogens, which can then be used for the development of pathogenic E. coli- specific mucosal vaccines.