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Reverse vaccinology of enterotoxigenic E. coli

产肠毒素大肠杆菌的反向疫苗学

基本信息

批准号：
8518225
负责人：
Philip Ross Hardwidge
金额：
$ 21.15万
依托单位：
KANSAS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8518225
关键词：
Adherence American Animal Model Antigens Basic Science Biological Assay Bioterrorism Categories Cell Culture Techniques Cell surface Child Developing Countries Diarrhea Disease Disease Outbreaks Drug Formulations Enterobacteriaceae Escherichia coli Escherichia coli Adhesins Escherichia coli Infections Escherichia coli Proteins Escherichia coli Vaccines Health Human Immune Sera Immune system Immunity Immunization In Vitro Infant Mortality Intestines Malnutrition Mediating Membrane Membrane Proteins Microbiology Military Personnel Modeling Mus National Institute of Allergy and Infectious Disease Performance Proteins Proteome Proteomics Recombinants Regimen Research Risk Scourge Source Surface Surface Antigens System Techniques Testing Vaccination Vaccine Antigen Vaccines Virulence Work burden of illness enteric pathogen enterotoxigenic Escherichia coli experience foodborne genome sequencing innovation neglect novel novel strategies novel therapeutics novel vaccines operation pathogen protective efficacy protein profiling research study vaccine candidate vaccine development vaccinology volunteer

项目摘要

DESCRIPTION (provided by applicant): Significance of the proposed research. Diarrheal disease caused by enteric bacteria is an important endemic health threat and a major source of food-borne disease. Diarrheal pathogens also remain an important health concern in current military operations and in bioterrorism. In spite of the appreciated magnitude of the threat to both general human health and the severe inhibition of military performance caused by ETEC, we still do not have an effective vaccine, nor do we fully understand the virulence determinants responsible for intestinal colonization and subsequent diarrheal disease. Basic research is needed to identify new therapeutic and vaccine targets. The objective of this application is to use quantitative proteomic protein profiling to discover broadly conserved antigens that will permit development of a vaccine efficacious against ETEC. The primary need that motivates this research objective is that despite the significant effort and expense that has been employed in vaccine trials using ETEC adhesins, none of these vaccines have been especially effective in mediating cross- protective immunity, and some trials have even had significant health risks. Alternative vaccine targets and strategies are demanded. We will utilize our proven experience in ETEC microbiology and quantitative proteomics to characterize novel ETEC vaccine antigens. We will do this by identifying novel surface-exposed ETEC proteins likely to be recognized by the host immune system. We show in preliminary studies that the proposed approach rapidly and economically identifies conserved, surface-exposed ETEC proteins, independent of strain-specific CFs, which can be purified and used in protection assays in a robust animal model of ETEC virulence. The specific aims are to: 1) Characterize ETEC outer membrane proteomes using quantitative proteomic profiling, 2) Produce recombinant ETEC proteins and antisera, and 3) Immunize mice with recombinant ETEC antigens and quantify their ability to protect against an otherwise lethal challenge with ETEC. The proposed research is significant and innovative because it introduces a novel strategy for protective antigen discovery for a neglected pathogen responsible for causing an enormous global diarrheal disease burden. Indeed, we have already discovered seventeen surface-exposed antigens that are potential components of a new ETEC vaccine formulation. Additionally, these experiments will optimize proteomic strategies needed to characterize vaccine candidates in other enteric pathogens.

描述（由申请人提供）：拟议研究的意义。由肠道细菌引起的腹泻病是一种重要的地方性健康威胁，也是食源性疾病的主要来源。腹泻病原体在当前的军事行动和生物恐怖主义中仍然是一个重要的健康问题。尽管人们认识到 ETEC 对一般人类健康的威胁程度以及对军事表现的严重抑制，但我们仍然没有有效的疫苗，我们也没有完全了解导致肠道定植和随后腹泻疾病的毒力决定因素。需要基础研究来确定新的治疗和疫苗靶点。本应用的目的是使用定量蛋白质组蛋白分析来发现广泛保守的抗原，从而开发出有效对抗 ETEC 的疫苗。推动这一研究目标的主要需求是，尽管在使用 ETEC 粘附素的疫苗试验中投入了大量的精力和费用，但这些疫苗在介导交叉保护性免疫方面都没有特别有效，而且一些试验甚至存在显着的健康风险。需要替代的疫苗目标和策略。我们将利用我们在 ETEC 微生物学和定量蛋白质组学方面的成熟经验来表征新型 ETEC 疫苗抗原。我们将通过鉴定可能被宿主免疫系统识别的新型表面暴露 ETEC 蛋白来做到这一点。我们在初步研究中表明，所提出的方法可以快速、经济地识别保守的、表面暴露的 ETEC 蛋白，不受菌株特异性 CF 的影响，可以在 ETEC 毒力的稳健动物模型中纯化并用于保护测定。具体目标是：1) 使用定量蛋白质组分析来表征 ETEC 外膜蛋白质组，2) 生产重组 ETEC 蛋白和抗血清，以及 3) 用重组 ETEC 抗原对小鼠进行免疫，并量化其抵御 ETEC 致命攻击的能力。这项拟议的研究具有重要意义和创新性，因为它引入了一种新策略，用于发现一种被忽视的病原体的保护性抗原，该病原体造成了巨大的全球腹泻疾病负担。事实上，我们已经发现了 17 种表面暴露抗原，它们是新 ETEC 疫苗配方的潜在成分。此外，这些实验将优化表征其他肠道病原体候选疫苗所需的蛋白质组学策略。