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）艰难梭菌是一种产芽孢病原体，可引起多种胃肠道 (GI) 疾病严重程度各异，从轻度腹泻到暴发性结肠炎直至死亡。治疗感染的困难传统抗生素的使用和反复感染率的增加强调了开发新药的必要性应对这一紧迫的公共卫生威胁的新治疗策略。迄今为止，艰难梭菌疫苗尚未上市完全满足这一需求，因此未来的战略将需要限制疾病和促进健康的创新方法清除这种病原体。我们的目标是建立一个管道来识别艰难梭菌上的新型疫苗抗原。艰难梭菌细胞和孢子表面，并将其开发为下一代多价 mRNA 疫苗艰难梭菌。抗原发现策略将纳入艰难梭菌生命周期的各个方面、抗原变异细胞表面和微生物生态。我们假设艰难梭菌蛋白的详细表征和基因系统对于受感染肠道的健康至关重要，并且与常驻微生物群的竞争将导致验证高效的新疫苗靶点。我们的方法将使用全基因组序列（WGS）和对各种医院和社区相关菌株进行表面蛋白质组分析并进行深入分析研究感染期间的代谢相关性。我们将结合先进的成像质谱技术 (IMS)、感染小鼠模型和遗传学来确定感染期间艰难梭菌的营养需求并针对这些表面暴露的蛋白质进行 mRNA-LNP 疫苗接种。这项工作将共同产生利用微生物生态学发现新疫苗靶点以根除病毒的转化工作流程艰难梭菌。