Function and immunogenicity of Yersinia pestis fimbriae

鼠疫耶尔森菌菌毛的功能和免疫原性

• 批准号: 6837119
• 负责人: Dieter M. Schifferli
• 金额: $ 31.7万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6837119
• 关键词: Escherichia coli; Salmonella; Yersinia pestis; Yersinia pestis disease; antibacterial antibody; bacterial genetics; bacterial vaccines; biotechnology; bioterrorism /chemical warfare; host organism interaction; immune response; laboratory mouse; molecular cloning; pilus; surface antigens; vaccine development

DESCRIPTION (provided by applicant): Yersinia pestis is the causative agent of Plague. Aerosolized Y. pestis is feared as a most dangerous bioweapon. There is currently no vaccine protecting humans against pneumonic Plague, the most contagious and lethal form of Plague. The long-term goal of this project is to develop a new, cost-effective vaccine capable of inducing mucosal and systemic immunity for extended protection against Plague. The studied major prototype vaccines against Y. pestis are based on only two subunit antigens, one not required for virulence. Such vaccines might not protect a sufficiently broad population of individuals with different genetic backgrounds. They also run the risk of becoming ineffective against naturally selected or engineered mutants of Y. pestis. The recently deciphered Y. pestis genome will be used to study additional immunogenic protein targets, preferably involved in some aspects of Y. pestis pathogenesis. The fimbrial proteins found in most if not all Enterobacteriaceae, including Y. pestis, are bestowed with such properties. Fimbriae are polymeric proteins assembled as hair-like organelles on bacterial surfaces. In addition to being among the best studied and most effective bacterial immunogens, many fimbriae are directly involved in mediating bacterial binding to host mucosal surfaces. Fimbriae induce typically high titers of both anti-bacterial and antiadhesive antibodies. They can be isolated in large amounts by simple methods, making them cost-effective vaccines. The first aim of this project is to clone each of the identified fimbrial gene clusters and to express the fimbriae on the surface of E. coli. Second, we will determine whether any of these fimbriae mediate E. coil binding to relevant epithelial cells or cells of the innate immune system. Third, in vivo expression of fimbriae will be determined by screening for antibodies in challenged mice. The importance of the fimbriae in pathogenesis will be studied with mutants. Fourth, mice will be immunized parenterally with fimbriae, and either orally or intra-nasally with an attenuated Salmonella vaccine strain expressing Y. pestis fimbriae. Systemic and mucosal humoral immune responses and the elicitation of anti-adhesive antibodies will be investigated. Challenge experiments will be undertaken to study immuno-protection by these vaccines.

描述（由申请人提供）：鼠疫耶尔森氏菌是鼠疫的病原体。雾化的鼠疫耶尔森氏菌被认为是最危险的生物武器。目前还没有疫苗可以保护人类免受肺鼠疫（鼠疫最具传染性和致命性的形式）的侵害。该项目的长期目标是开发一种新的、具有成本效益的疫苗，能够诱导粘膜和全身免疫，以延长对鼠疫的保护。所研究的针对鼠疫耶尔森氏菌的主要原型疫苗仅基于两种亚基抗原，其中一种亚基抗原不需要毒力。此类疫苗可能无法保护足够广泛的具有不同遗传背景的个体群体。它们还面临着对自然选择或工程改造的鼠疫杆菌突变体无效的风险。最近破译的鼠疫耶尔森氏菌基因组将用于研究其他免疫原性蛋白质靶标，最好涉及鼠疫耶尔森氏菌发病机制的某些方面。大多数肠杆菌科细菌（包括鼠疫杆菌）中发现的菌毛蛋白都具有这种特性。菌毛是在细菌表面组装成毛发状细胞器的聚合蛋白。除了是研究最透彻和最有效的细菌免疫原之一之外，许多菌毛还直接参与介导细菌与宿主粘膜表面的结合。菌毛通常诱导高滴度的抗菌和抗粘附抗体。它们可以通过简单的方法大量分离，从而成为具有成本效益的疫苗。该项目的首要目标是克隆每个已识别的菌毛基因簇并在大肠杆菌表面表达菌毛。其次，我们将确定这些菌毛是否介导大肠杆菌与相关上皮细胞或先天免疫系统细胞的结合。第三，菌毛的体内表达将通过筛选受攻击的小鼠中的抗体来确定。菌毛在发病机制中的重要性将通过突变体进行研究。第四，用菌毛对小鼠进行肠胃外免疫，并用表达鼠疫菌菌毛的减毒沙门氏菌疫苗株口服或鼻内免疫。将研究全身和粘膜体液免疫反应以及抗粘附抗体的引发。将进行攻击实验来研究这些疫苗的免疫保护作用。