Developing effective nanovaccines against pathogenic Escherichia coli

摘要 我们在致病性大肠杆菌研究领域的科学贡献是加速了 利用新的抗原和小鼠肠道感染模型，开发一种有效的疫苗，可以 既可预防肠出血性大肠杆菌O157：H7，又可防止其他细菌定植 致病性大肠杆菌感染。因此，我们研究的长期目标是提供新的基础 关于致病性大肠杆菌定植的知识，同时阐明保护性免疫反应可以 被纳入到疫苗的开发中。我们建议的中心假设是新的抗原 与纳米疫苗结合将是免疫原性的，保护性抗体的刺激将扰乱定植 由不同的致病性大肠杆菌菌株所致。这一假设是建立在强有力的实验前提之上的 证明金纳米颗粒偶联到表面暴露的EHEC抗原(由我们的生物- 免疫信息学方法)引起与肠道减少相关的宿主免疫反应 肠出血性大肠杆菌O157：H7的定植。我们近年来的进展表明，将抗原偶联到黄金上 纳米粒显著增强对EHEC O157：H7感染的保护性免疫力，而来自 接种疫苗的小鼠降低了致病性大肠杆菌O127：H6和肠聚集性大肠杆菌的粘附性/毒力。 ColiO104：H4。我们建议的实验方法将集中在两个可重现和科学合理的 目标：优化一种含有预防EHEC感染的抗原的金纳米疫苗(目标1)，以及 阐明防止定植所需的免疫反应，并测试针对 其他致病性大肠杆菌菌株(目标2)。这项工作意义重大，因为它有望提供进步 正在开发一种完全保护性的金纳米疫苗，以防止由EHEC引起的感染 O157：H7，这种疫苗也将有效地针对其他致病性大肠杆菌菌株，而不需要 影响共生的大肠杆菌微生物区系。这项研究将阐明毒力之间的共同联系。 这些细菌病原体的机制，然后可以用来发展致病性大肠杆菌- 特定的粘膜疫苗。

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.