Developing effective nanovaccines against pathogenic Escherichia coli

开发针对致病性大肠杆菌的有效纳米疫苗

• 批准号: 10300897
• 负责人: Alfredo G Torres
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300897
• 关键词: Adherence; Affect; Antibodies; Antibody titer measurement; Antigens; Attention; Bacteria; Binding; Cells; Child; Coupled; Couples; Coupling; Data; Development; Diarrhea; Disease; Disease Outbreaks; Epithelial Cells; Escherichia coli; Escherichia coli EHEC; Escherichia coli Infections; Escherichia coli O157:H7; Fimbrial Adhesins; Food; Formulation; Goals; Hemolytic-Uremic Syndrome; Hemorrhagic colitis; Human; Immune response; Immunity; Immunization; Immunize; Infection; Infection prevention; Injections; Intestines; Knowledge; Lesion; Link; Mediating; Mucosal Immune Responses; Mus; Outcome; Pilum; Play; Preventive; Process; Property; Proteins; Reproducibility; Research; Role; Serotyping; Serum; Shiga Toxin; Subunit Vaccines; Surface; Testing; Toxin; Type III Secretion System Pathway; Vaccinated; Vaccines; Variant; Vegetables; Virulence; Virulence Factors; Virulent; Work; base; beef; biothreat; combat; diarrheal disease; enteric infection; enteric pathogen; enteroaggregative Escherichia coli; enteropathogenic Escherichia coli; experimental study; foodborne pathogen; gut colonization; immunogenic; improved; innovation; insight; intestinal epithelium; microbiota; mouse model; mucosal vaccine; nanoGold; nanovaccine; novel; pathogen; pathogenic Escherichia coli; pathogenic bacteria; prevent; sound; tissue tropism; vaccine development

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.

抽象的 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一种有效的疫苗，可以 不仅可以预防肠出血性大肠杆菌 (EHEC) O157:H7，还可以防止其他细菌定植 致病性大肠杆菌感染。因此，我们研究的长远目标是提供新的基础 有关致病性大肠杆菌定植的知识，同时阐明可以 被纳入疫苗的开发中。我们提案的中心假设是新抗原 与纳米疫苗结合将具有免疫原性，保护性抗体的刺激将破坏定植 由不同的致病性大肠杆菌菌株引起。这个假设是基于强有力的实验前提 证明金纳米颗粒与表面暴露的肠出血性大肠杆菌抗原（由我们的生物定义）偶联 免疫信息学方法）引发了与肠道菌群减少相关的宿主免疫反应 EHEC O157:H7 定植。我们近年来的进展表明，将抗原与金偶联 纳米颗粒显着增强对 EHEC O157:H7 感染的保护性免疫力，并且血清 接种疫苗的小鼠可降低肠道致病性大肠杆菌 O127:H6 和肠聚集性大肠杆菌的粘附/毒力。 大肠杆菌 O104:H4。我们提出的实验方法将重点关注两种可重复且科学合理的方法 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），以及 阐明防止定植所需的免疫反应并测试针对细菌的交叉保护特性 其他致病性大肠杆菌菌株（目标 2）。这项工作很重要，因为它有望带来进步 开发一种完全保护性的金纳米颗粒疫苗，可预防肠出血性大肠杆菌引起的感染 O157:H7，这样的疫苗也将有效地针对其他致病性大肠杆菌菌株，而无需 影响共生大肠杆菌微生物群。这项研究将阐明毒力的共同联系 这些细菌病原体的机制，然后可用于致病性大肠杆菌的开发 特异性粘膜疫苗。