Project 2: Leveraging microbial ecology to define novel Clostridioides difficile mRNA vaccine targets

项目 2：利用微生物生态学确定新的艰难梭菌 mRNA 疫苗靶标

基本信息

批准号：
10625578
负责人：
Joseph Paul Zackular
金额：
$ 41.63万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625578
关键词：
Adult Age Anatomy Antibiotics Antigen Targeting Antigenic Variation Antigens Biological Response Modifier Therapy Cell surface Cells Cessation of life Childhood Clinical Clostridium difficile Colitis Collaborations Combined Modality Therapy Communities Complex Development Diarrhea Disease Ecology Ecosystem Exposure to Future Gastrointestinal Diseases Gastrointestinal tract structure Genes Genetic Genetic Transcription Genome Genomics Germ-Free Healthcare Hospitals Immune response Immunity Infection Investigation Laboratories Libraries Life Cycle Stages Maps Mediating Messenger RNA Metabolic Metalloproteases Mutagenesis Nutrient Nutritional Requirements Nutritional Study Outcome Patients Phase Phenotype Play Population Prevention Primary Infection Primary Prevention Proteins Proteome Proteomics Public Health RNA vaccination RNA vaccine Reporter Reproduction spores Role Severities Surface System Therapeutic Toxin Vaccination Vaccine Antigen Vaccines Validation Work bioinformatics pipeline clinically relevant cohort combat design fecal transplantation fitness gene conservation gut colonization innovation insight mass spectrometric imaging microbial microbial community microbial composition microbiota mouse model next generation novel novel therapeutic intervention novel vaccines pathogen prevent rational design recurrent infection relapse prevention success targeted treatment transcriptomics transposon sequencing uptake vaccine development vaccine efficacy vaccine strategy whole genome

项目摘要

SUMMARY - PROJECT 2 (ANTIGEN DISCOVERY) Clostridium difficile is a spore-forming pathogen that causes a wide range of gastrointestinal (GI) disorders varying in severity from mild diarrhea to fulminant colitis and death. Difficulties in treating infections with conventional antibiotics and increasing rates of recurrent infection underscore the need for the development of new therapeutic strategies to combat this urgent public health threat. To date vaccines for C. difficile have not fully met this need, thus future strategies will require innovative approaches that limit disease and promote clearance of this pathogen. Our objective is to generate a pipeline to identify novel vaccine antigens on the C. difficile cell and spore surface and develop these as the next generation of multi-valent mRNA vaccines against C. difficile. Antigen discovery strategy will incorporate aspects of the C. difficile life cycle, antigen variation on the cell surface, and microbial ecology. We hypothesize that detailed characterization of C. difficile proteins and gene systems important for fitness in the infected gut and competition with the resident microbiota will lead to validation of highly effective new vaccine targets. Our approach will use whole genome sequence (WGS) and surface proteome analyses on a wide array of hospital and community-associated strains and in-depth investigation into metabolic correlates during infection. We will combine advanced imaging mass spectrometry (IMS), mouse models of infection, and genetics to define nutritional requirements for C. difficile during infection and target these surface exposed proteins for mRNA-LNP vaccination. Together, this work will generate a translational workflow that leverages microbial ecology for discovery of novel vaccine targets for eradication of C. difficile.

摘要 - 项目2（抗原发现）艰难梭菌是一种形成孢子的病原体，会引起广泛的胃肠道（GI）疾病从轻度腹泻到暴发性结肠炎和死亡的严重程度各不相同。治疗感染的困难常规抗生素和复发感染率的提高强调了开发的需求应对这种紧急公共卫生威胁的新治疗策略。迄今为止，艰难梭菌的疫苗还没有完全满足了这一需求，因此未来的策略将需要限制疾病并促进疾病的创新方法该病原体的清除。我们的目标是生成一条管道，以鉴定C上的新型疫苗抗原。艰难的细胞和孢子表面并将其发展为下一代多价mRNA疫苗针对艰难梭菌。抗原发现策略将结合艰难梭菌生命周期的各个方面，抗原变化细胞表面和微生物生态学。我们假设艰难梭菌蛋白和对于感染肠道和与居民微生物群竞争至关重要的基因系统将导致验证高效的新疫苗靶标。我们的方法将使用整个基因组序列（WGS）和在广泛的医院和社区相关菌株和深入的表面蛋白质组分析在感染期间对代谢相关的研究。我们将结合高级成像质谱法（IMS），感染的小鼠模型和遗传学，以定义感染过程中艰难梭菌的营养需求并靶向这些表面暴露的蛋白进行mRNA-LNP疫苗接种。一起，这项工作将产生转化工作流程利用微生物生态学来发现新型疫苗靶标的根除艰难梭菌。