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

• 批准号: 7186011
• 负责人: JUN LIN
• 金额: $ 16.63万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-20 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7186011
• 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

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）：空肠弯曲杆菌是 NIAID B 类优先病原体，是美国人类肠炎的主要原因，对公众健康构成重大威胁。过去十年来，弯曲杆菌对临床抗生素的耐药性不断增加，迫切需要开发替代干预策略，例如疫苗接种，以预防和控制弯曲杆菌感染。尽管最近在阐明空肠弯曲菌中的免疫原性和保护性抗原方面取得了进展，但针对空肠弯曲菌定植的动物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有待确定。 R21 应用的主要目标是开发和评估针对空肠弯曲菌的新型亚单位疫苗 CmeC。空肠弯曲菌的外膜蛋白（OMP）被认为是病原体与宿主相互作用的主要介质，因此是设计保护性疫苗的有希望的候选者。最近，我们在弯曲杆菌中鉴定了独特的 OMP CmeC。作为多药外排系统 CmeABC 的关键组成部分，CmeC 有助于弯曲杆菌对多种抗菌药物产生耐药性，并且通过介导胆汁耐药性对于弯曲杆菌在动物肠道中定植也至关重要。 CmeC 作为一种体内免疫原性 OMP，在各种弯曲杆菌菌株中广泛分布和组成型表达。特别地，CmeC的表达受到肠道中存在的胆汁盐的显着诱导。基于这些观察，我们假设 CmeC 是一种用于针对弯曲杆菌感染进行免疫干预的新型亚单位候选疫苗。为了检验我们的假设，我们计划 i) 检查原代弯曲杆菌分离株中 CmeC 的序列多态性、抗原同源性和体外免疫保护； ii) 评估新型亚单位 CmeC 疫苗在空肠弯曲菌感染鸡模型中的免疫原性和保护功效； 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，我们期望获得有关以 CmeC 为靶点对人类弯曲杆菌感染进行免疫保护的可行性的关键信息。 CmeC独特的肠道定植和抗生素耐药双重功能极大地提高了该应用的创新性和意义。相关性：空肠弯曲杆菌是美国最常见的引起人类胃肠炎的食源性细菌病原体。拟议的研究将为开发有效的空肠弯曲杆菌疫苗以保护公众健康提供新的信息。