Targeting Heme Transporters for Improved Vaccines against Anthrax

针对血红素转运蛋白改进炭疽疫苗

基本信息

批准号：
8823908
负责人：
ANTHONY W MARESSO
金额：
$ 23.69万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8823908
关键词：
Animal Model Animals Anthrax Vaccine Absorbed Anthrax Vaccines Anthrax disease Antibiotics Antibodies Antibody Response Antigens Attenuated Bacillus (bacterium)Bacillus anthracis Bacillus anthracis spore Bacteria Bacterial Proteins Binding Biological Biological Assay Bioterrorism Carrier Proteins Cattle Cavia Cells Cessation of life Clostridium Containment Data Development Disease Drops Elements Failure Genus staphylococcus Gram-Positive Bacteria Growth Health Heme Heme Iron Hemoglobin Hydrogen Industry Infection Iron Iron Uptake Inhibition Knowledge Laboratories Life Listeria Mammals Marketing Mediating Modeling Molecular Mus Mutagenesis Nutrient Opsonin Oxygen Pathogenesis Porphyrins Process Proteins Recombinants Reproduction spores Research Soldier Specificity Staphylococcus aureus Streptococcus Testing Toxin Vaccination Vaccines Virulence Virulent Work aerosolized anthrax toxin immunogenicity improved innovation killings mortality novel novel vaccines pathogen pathogenic bacteria phase II trial prevent programs protective effect protein function public health relevance response uptake vaccine candidate vaccine development vaccine efficacy vaccinology

项目摘要

DESCRIPTION (provided by applicant): There may not be a more significant biological threat than the malevolent release of B. anthracis spores, the causative agent of anthrax disease, over a major metropolis. With the inhalational form approaching 90% mortality, and a spore that can remain infectious for years, protection against this deadly disease is critical. The U.S. anthrax vaccine induces toxin-neutralizing protection in animal models. However, its composition is unknown, its immunogenicity is short-lived, and it does not protect against some strains of B. anthracis. Our preliminary data suggests bacillus near-iron transporter (NEAT) proteins, which function to acquire and import host heme during infection, can protect mice against anthrax disease following vaccination. In this application, we use our molecular understanding of NEAT protein function to create and test a novel vaccine composed of heme transporters. We hypothesize vaccination with bacillus NEAT proteins will induce neutralizing or opsonin-mediated responses to B. anthracis and protect vertebrate hosts from full-blown anthrax after infection with the most highly-virulent strains. Aim 1: Determine the mechanism of protection following vaccination with NEAT proteins. Recombinant NEAT domains will be evaluated for efficacy using a murine model of anthrax. Protective antibodies will be evaluated for activity using heme acquisition and opsonin-mediated assays. Aim 2: Determine if vaccination with NEAT proteins protects against fully-virulent B. anthracis. NEAT proteins will be evaluated for their ability to protect against fully-virulent B. anthracis using a well-accepted guinea pig model of anthrax under high-containment. Safe antigens will also be constructed by mutagenesis of key residues that mediate NEAT functionality. Since NEAT proteins are conserved in every major genus of Gram-positive pathogenic bacteria, this work also has universal appeal for vaccine development against related species.

描述（由申请人提供）：比主要的大都市对炭疽病的恶性释放（炭疽病的恶性释放）可能没有更大的生物学威胁。随着吸入形式接近90％的死亡率，并且可以保持传染性多年的孢子，对这种致命疾病的保护至关重要。美国炭疽疫苗在动物模型中诱导毒素中和保护。但是，其组成尚不清楚，其免疫原性是短暂的，并且不能防止某些炭疽芽孢杆菌菌株。我们的初步数据表明，在感染过程中获取和进口宿主血红素的功能和进口宿主血红素的杆菌近铁蛋白可以保护小鼠免受疫苗接种后的炭疽病疾病。在此应用中，我们使用对纯蛋白功能的分子理解来创建和测试由血红素转运蛋白组成的新型疫苗。我们假设用纯种蛋白质疫苗接种疫苗将诱导对炭疽芽孢杆菌的中和蛋白介导的反应，并保护脊椎动物宿主在感染最高度毒性的菌株后免受全面的炭疽病。目标1：确定用纯蛋白接种后的保护机理。使用炭疽的鼠模型，将评估重组整洁域的功效。将使用血红素获取和opsonin介导的测定法评估保护性抗体的活性。 AIM 2：确定纯蛋白疫苗是否可以防止炭疽病的全斑。将评估整洁的蛋白质的能力，可以使用良好认可的豚鼠模型来防止炭疽病的全虫链球菌。在高管下的炭疽病。安全抗原也将通过介导整洁功能的关键残基的诱变来构建。由于在革兰氏阳性致病细菌的每个主要属中纯蛋白都是保守的，因此这项工作还普遍吸引了针对相关物种的疫苗开发。