Development and evaluation of subunit vaccine CmeC against Campylobacter jejuni

空肠弯曲菌亚单位疫苗CmeC的研制及评价

基本信息

批准号：
7497096
负责人：
JUN LIN
金额：
$ 16.31万
依托单位：
UNIVERSITY OF TENNESSEE KNOXVILLE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-20 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7497096
关键词：
Acute Address Animal Model Animals Antibiotic Resistance Antibiotics Antibodies Antigens Bacteria Bacterial Outer Membrane Proteins Bile fluid Campylobacter Campylobacter infection Campylobacter jejuni Categories Cessation of life Chickens Clinical Condition Developed Countries Development Drug resistance Ensure Evaluation Foundations Gastroenteritis Genetic Polymorphism Genome Goals Guillain-Barré Syndrome Human Immune In Vitro Infection Intervention Intestines Lead Macrolides Mediating Mediator of activation protein Membrane Proteins Modeling Molecular National Institute of Allergy and Infectious Disease Operon Organism Outcome Paralysed Pathogenesis Pharmacologic Substance Positioning Attribute Prevalence Protein C Public Health Publishing Pump Regulation Research Research Personnel Resistance Respiratory Muscles Reverse Transcriptase Polymerase Chain Reaction Role Solid Subunit Vaccines System Testing Time United States Vaccination Vaccines Work antimicrobial base bile salts clinical efficacy design efflux pump enteritis experience foodborne immunogenic immunogenicity improved in vivo innovation novel novel vaccines pathogen prevent programs protective effect success tool vaccine development

项目摘要

DESCRIPTION (provided by applicant): Campylobacter jejuni, a NIAID Category B Priority Pathogen, is the leading bacterial cause of human enteritis in the United States and presents a major threat to public health. Increasing resistance of Campylobacter to clinical antibiotics in the past decade raised an urgent demand for the development of alternative intervention strategies, such as vaccination, to prevent and control Campylobacter infections. Despite recent progress on the elucidation of immunogenic and protective antigens in C. jejuni, vaccination of animals against C. jejuni colonization had only partial success and the immunogenic antigens with significant protective effect remain to be determined. The main goal of this R21 application is to develop and evaluate a novel subunit vaccine CmeC against C. jejuni. Outer membrane proteins (OMPs) of C. jejuni are considered the major mediators of the pathogen-host interaction, as a consequence, the promising candidates for the design of protective vaccines. Recently, we have characterized a unique OMP CmeC in Campylobacter. As a key component in multidrug efflux system CmeABC, CmeC contributes Campylobacter resistance to a broad spectrum of antimicrobials and is also essential for Campylobacter colonization in animal intestine by mediating bile resistance. As an immunogenic OMP in vivo, CmeC is widely distributed and constitutively expressed among various Campylobacter strains. Particularly, expression of CmeC is dramatically induced by bile salts present in intestine. Based on these observations, we hypothesize that CmeC is a novel subunit vaccine candidate for immune intervention against Campylobacter infections. To test our hypothesis, we plan to i) examine sequence polymorphism, antigenic homology, and in vitro immune protection of CmeC in primary Campylobacter isolates; ii) evaluate the immunogenicity and protective efficacy of a novel subunit CmeC vaccine in a chicken model of C. jejuni infection; and iii) determine the role of CmeC vaccine in potentiating the efficacy of clinical antibiotics. Once the proposed studies are completed, we expect to obtain critical information on the feasibility of targeting CmeC for immune protection against Campylobacter infections in humans. The unique dual functions of CmeC in intestinal colonization and antibiotic resistance greatly improve innovative aspect and significance of this application. Relevance: Campylobacter jejuni is the most prevalent foodborne bacterial pathogen causing human gastroenteritis in the U.S. The proposed research will provide novel information on the development of effective vaccine against C. jejuni to protect public health.

描述（由申请人提供）：B曲杆菌Jejuni是B级优先病原体，是美国人类肠炎的主要原因，并对公共卫生构成了主要威胁。在过去的十年中，弯曲杆菌对临床抗生素的耐药性提高了迫切需求，以开发替代干预策略，例如疫苗接种，以预防和控制弯曲杆菌感染。尽管最近在空肠梭菌中阐明免疫原性和保护性抗原方面的进展，但动物对空肠梭菌的疫苗接种仅取得了部分成功，并且具有显着保护作用的免疫原性抗原仍然有待确定。该R21应用程序的主要目标是开发和评估针对Jejuni的新型亚基疫苗CMEC。因此，空肠梭状芽胞杆菌的外膜蛋白（OMP）被认为是病原体宿主相互作用的主要介体，因此，有希望的保护性疫苗设计的有前途的候选者。最近，我们在弯曲杆菌中表征了独特的OMP CMEC。作为多重外排系统CMEABC的关键组成部分，CMEC对弯曲杆菌的抗性能力对广泛的抗微生物剂产生耐药性，并且通过介导胆汁耐药性，对于动物肠道中的弯曲杆菌定植也是必不可少的。作为一种免疫原性体内，CMEC在各种弯曲杆菌菌株中被广泛分布并组成式表达。特别是，CMEC的表达是由肠中存在的胆汁盐巨大诱导的。基于这些观察结果，我们假设CMEC是一种新型的亚基疫苗候选候选，用于针对弯曲杆菌感染的免疫干预。为了检验我们的假设，我们计划i）检查序列多态性，抗原同源性和在原代弯曲杆菌分离株中CMEC的体外免疫保护； ii）评估新型亚基CMEC疫苗在空肠梭菌感染的鸡模型中的免疫原性和保护性疗效； iii）确定CMEC疫苗在增强临床抗生素功效中的作用。一旦拟议的研究完成，我们希望获得有关针对人类弯曲杆菌感染的CMEC免疫保护的可行性的关键信息。 CMEC在肠道定植和抗生素耐药性中的独特双重功能极大地改善了该应用的创新方面和意义。相关性：弯曲杆菌是美国最普遍的食源性细菌病原体，导致人类胃肠炎，拟议的研究将提供有关开发有效疫苗针对Jejuni的有效疫苗以保护公共卫生的新信息。