Acquired Immunity and Vaccination for P. aeruginosa

铜绿假单胞菌的获得性免疫和疫苗接种

基本信息

批准号：
7571643
负责人：
Gerald B Pier
金额：
$ 34.17万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1984
资助国家：
美国
起止时间：
1984-12-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7571643
关键词：
Acute Pneumonia Address Antibodies Antigens Attenuated Attenuated Live Virus Vaccine Attenuated Vaccines Cellular Immunity Chronic Communities Cornea Cystic Fibrosis Transmembrane Conductance Regulator Cytotoxic T-Lymphocytes Development Epithelial Cells Epitopes Evaluation Eye Eye Infections Genes Goals Humoral Immunities Immune Immune system Immunity Immunization Infection Ingestion Interruption Keratitis Life Lipopolysaccharides Lung Modeling Molecular Mus Nosocomial pneumonia O Antigens Organism Oropharyngeal Passive Immunization Pathogenesis Phase Polyvalent Vaccine Prevention Pseudomonas aeruginosa Reagent Resistance Resistance to infection Side Staging Surface System T-Lymphocyte Technology Testing Tissues Transgenic Organisms Vaccination Vaccines Virulence Virulence Factors Work acquired immunity base cell killing cystic fibrosis mouse cytotoxic design extracellular gastrointestinal insight killings mutant transposon site hybridization vaccine evaluation

项目摘要

DESCRIPTION (provided by applicant): The major goals of this project are to understand basic aspects of virulence and host immunity to lipopolysaccharide (LPS)-smooth strains of P. aeruginosa that are major causes of hospital acquired pneumonia and community-acquired bacterial keratitis of the eye. The primary hypothesis to be evaluated is that effective immunity to P. aeruginosa will require the use of immunogens that elicit both antibodies and cytotoxic T cells (CTL) that can kill extracellular and intracellular P. aeruginosa. In regard to immunity to the extracellular stage of pathogenesis, for many P. aeruginosa strains, effective humoral immunity requires antibodies that recognize highly variable subtype-specific epitopes on the LPS O side chain. Subtype epitope variability greatly increases the number of antigens that need to be incorporated into a vaccine that go beyond the 20 major LPS-based serogroups of P. aeruginosa. More problematic has been the difficulty in inducing such antibodies by LPS-O antigen based immunogens. Appropriate LPS-specific antibodies cannot readily be elicited with polyvalent vaccines because of antagonistic interactions among structurally-related immunogens and the host immune system, so newer antigen-delivery systems are needed. To address this need we are focusing on producing and testing live, attenuated P. aeruginosa vaccines that would be better immunogens for inducing LPS specific protective antibody and also provide immunity to the intracellular phase of P. aeruginosa infection that has recently been documented. P. aeruginosa enters epithelial cells via the cystic fibrosis transmembrane conductance regulator (CFTR) during the course of lung and eye infections, and epithelial cell ingestion has a significant impact on the organism's ability to cause infections. The major aim of the proposal will be to explore how attenuated vaccines that enter lung epithelial cells prior to clearance induce protective antibodies and T cells that recognize infected epithelial cells and kill the intracellular P. aeruginosa. Overall, the aims are designed to gain a better understanding of how to elicit protective immunity to P. aeruginosa, focusing on use of attenuated strains to provoke humoral and cell-mediated immunity (CMI) against both cytotoxic and noncytotoxic P. aeruginosa strains. Specific questions to be addressed include: 1) can attenuated strains of P. aeruginosa be safely produced that elicit humoral and cellular immune effectors that kill P. aeruginosa outside and inside of epithelial cells?; 2) can such vaccines elicit broadly-based acquired resistance to P. aeruginosa infection; and, 3) how is CMI elicited by attenuated vaccines and how does this immune effector contribute to resistance to infection? The results of this work should further our insights into P. aeruginosa pathogenesis, development of acquired immunity and the potential to develop effective reagents for active and passive immunization to augment the prevention and treatment off, aeruginosa infections.

描述（由申请人提供）：该项目的主要目标是了解毒力和宿主对脂多糖（LPS） - 铜绿假单胞菌的平滑菌株的基本方面，这些菌株是医院获得的肺炎和社区获得的细菌性细菌性角膜炎的主要原因。要评估的主要假设是，对铜绿假单胞菌的有效免疫力将需要使用引起抗体和细胞毒性T细胞（CTL）的免疫原子（CTL），以杀死细胞外和细胞内铜绿假单胞菌。对于对许多铜绿假单胞菌菌株的细胞外阶段的免疫力，有效的体液免疫需要抗体，这些抗体在LPS O侧链上识别高度可变的亚型特异性表位。亚型表位变异性大大增加了需要掺入需要掺入超出20个主要LPS基于LPS的铜绿假单胞菌的抗原的数量。更有问题的是难以通过基于LPS-O抗原免疫原的诱导此类抗体。由于结构相关的免疫原子和宿主免疫系统之间的拮抗相互作用，因此无法通过多价疫苗引起适当的LPS特异性抗体，因此需要更新的抗原分散系统。为了满足这一需求，我们专注于生产和测试实时，减弱的铜绿假单胞菌疫苗，这将是诱导LPS特异性保护抗体的更好的免疫原子，并且还对铜绿假单胞菌感染的细胞内相提供了免疫力。铜绿假单胞菌在肺部和眼部感染过程中通过囊性纤维化跨膜电导调节剂（CFTR）进入上皮细胞，并且上皮细胞摄入对生物体引起感染的能力有重大影响。该提案的主要目的是探索如何在清除诱导识别感染上皮细胞并杀死细胞内铜绿假单胞菌的保护性抗体和T细胞之前探索如何进入肺上皮细胞的疫苗。总体而言，这些目标旨在更好地了解如何引起对铜绿假单胞菌的保护性免疫，重点是使用衰减菌株来引起对细胞毒性和非糖毒性毒素毒素毒素菌株的体液和细胞介导的免疫（CMI）。要解决的具体问题包括：1）可以安全地产生铜绿假单胞菌的菌株，从而引起杀死铜绿假单胞菌在上皮细胞外部和内部的体液和细胞免疫效应子？ 2）这种疫苗可以引起广泛的获得铜绿假单胞菌感染的耐药性； 3）如何通过减毒疫苗引起CMI，该免疫效应子如何促进感染的抗性？这项工作的结果应进一步洞悉铜绿假单胞菌的发病机理，获得的免疫力的发展以及开发有效试剂进行主动和被动免疫的潜力，以增强预防和治疗的铜绿感染。