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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.

总结-项目2（抗原发现）艰难梭菌是一种孢子形成病原体，可引起广泛的胃肠道（GI）疾病严重程度从轻度腹泻到暴发性结肠炎和死亡不等。治疗感染的困难常规抗生素和复发感染率的增加强调了开发新的治疗策略，以应对这一紧迫的公共卫生威胁。迄今为止，C.艰难没有因此，未来的战略将需要采取创新的方法，限制疾病，清除这种病原体。我们的目标是产生一个管道，以确定新的疫苗抗原的C。艰难梭菌细胞和孢子表面，并开发这些作为下一代多价mRNA疫苗， C.很难抗原发现策略将结合C.艰难梭菌生命周期，抗原变异细胞表面和微生物生态学。我们假设C.艰难蛋白和对受感染肠道的适应性和与常驻微生物群的竞争很重要的基因系统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），对广泛的医院和社区相关菌株进行表面蛋白质组分析，研究感染期间的代谢相关性。我们将联合收割机先进的成像质谱 (IMS)、小鼠感染模型和遗传学来确定C.感染期间的艰难并靶向这些表面暴露的蛋白质用于mRNA-LNP疫苗接种。总之，这项工作将产生一个利用微生物生态学发现新的疫苗靶点， C.很难