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Identifying the Breadth of Antibody Responses to Clostridioides difficile Infection

确定抗体对艰难梭菌感染反应的广度

基本信息

批准号：
10186695
负责人：
LARRY K KOCIOLEK
金额：
$ 7.84万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-09 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10186695
关键词：
Adult Animal Model Animals Antibodies Antibody Response Antigen Targeting Antigens Cells Centers for Disease Control and Prevention (U.S.)Child Childhood Clinical Clostridium difficile Colitis Communicable Diseases Data Databases Development Diarrhea Environment Enzyme-Linked Immunosorbent Assay Epitopes FDA approved Feasibility Studies Future Genes Genome Genomics Goals Health Expenditures Human Immune Immune response Immunization Immunocompetent Immunoglobulins Immunologics Immunotherapy In Vitro Individual Infection Infection prevention Investigation Knowledge Life Light Link Methods Microbiology Molecular Epidemiology Monoclonal Antibodies Morbidity - disease rate Mucocutaneous Lymph Node Syndrome Pathogenesis Patients Pediatric Hospitals Plasma Cells Plasmablast Prevention strategy Preventive therapy Protein Fragment Proteins Proteome Proteomics Public Health Recurrence Research Resources Reverse Transcriptase Polymerase Chain Reaction Risk Testing Toxin Transfection Transgenic Mice Translating Universities Vaccination Vaccine Antigen Vaccines Vibrio cholerae Vibrio cholerae infection Work base career development clinical development clinical epidemiology clinical investigation cohort design diarrheal disease expression vector healthcare-associated infections human monoclonal antibodies immunogenic immunogenicity improved innovation mortality novel pathogen peripheral blood preclinical study prevent public health relevance recurrent infection response skills synthetic antibodies tandem mass spectrometry therapeutically effective transmission process whole genome

项目摘要

PROJECT SUMMARY ABSTRACT Clostridioides (Clostridium) difficile infection (CDI) is a common healthcare-associated infection in US children and adults. CDI, which ranges from mild diarrhea to life-threatening colitis, is associated with substantial morbidity, mortality, and excess healthcare expenditures. The CDC has classified C. difficile as an “immediate public health threat that requires urgent and aggressive action.” This call to action has expanded CDI investigation and prompted efforts to develop novel and more effective prevention strategies. Immunological agents are a promising strategy for CDI prevention; a monoclonal antibody against C. difficile is recently FDA approved for CDI prevention, and several toxin-based vaccines are in clinical development. Despite these products showing promise for CDI prevention, many patients have failed these therapies. The immunizations currently under clinical investigation were developed based on knowledge of C. difficile immunogenicity in animals, which may not adequately represent C. difficile immunogenicity in humans. To better understand the relative immunogenicity of C. difficile antigens in humans, we propose characterization of the plasmablast response following natural CDI. Plasmablasts are plasma cell precursors that produce antibodies directed against a pathogen; antigen-specific plasmablasts can be isolated from peripheral blood 1-3 weeks after infection. Antibodies encoded by these cells can be produced in vitro and the target antigens identified. This innovative method has been recently successfully applied to other infectious diseases, including to Kawasaki Disease by our research team. By analyzing the plasmablast response following CDI, we will identify the breadth of the human antibody response to C. difficile infection. We hypothesize that the antibody response to C. difficile is not limited to toxin antigens, and that antibodies against both toxin and non-toxin antigens provide protection against CDI. Specifically, in this feasibility study, we aim to identify and clone the peripheral blood plasmablast response following CDI in 3 children and 3 adults, and identify C. difficile antigenic targets of oligoclonal post-CDI plasmablasts using various proteomics analyses. Knowledge gained in this feasibility study will inform design of larger studies to validate immunogenicity of C. difficile antigens in a more diverse patient cohort and the neutralizing ability of these antibodies across a diverse set of C. difficile strain types. In future studies, we will determine the specific toxin and non-toxin epitopes recognized by antibodies following natural CDI in humans, and we will study how antibody responses to C. difficile toxin and non-toxin antigens impact C. difficile colonization and infection. Identification of broadly immunogenic antigens will guide future work to investigate potential immunization candidates to prevent CDI and colonization. Our research team and the Northwestern University academic environment possess the skills and resources, respectively, that are necessary for successful completion of the proposed studies, including assembly of patient cohort, bacterial genomics, plasmablast isolation, plasmablast antibody synthesis, and proteomics. !

项目摘要艰难梭菌感染（CDI）是美国儿童常见的医疗保健相关感染和成年人。CDI，范围从轻度腹泻到危及生命的结肠炎，与大量的发病率、死亡率和过度医疗支出。疾控中心将其归类为C类。作为一个“立即公共卫生威胁，需要采取紧急和积极的行动。”这一行动呼吁扩大了土发委会调查和促进努力制定新的和更有效的预防战略。免疫药物是预防CDI的一种有前途的策略; FDA最近已批准用于预防CDI，并且几种基于毒素的疫苗正在临床开发中。尽管有这些虽然这些产品显示出预防CDI的前景，但许多患者在这些治疗中失败了。免疫接种目前正在临床研究中，基于对C.免疫原性动物，这可能不足以代表C。免疫原性。更好地了解 C.相对免疫原性人类中的艰难抗原，我们建议对浆母细胞进行表征自然CDI反应。浆母细胞是浆细胞前体，其产生针对抗病原体;抗原特异性浆母细胞可以在抗病原体后1-3周从外周血中分离感染由这些细胞编码的抗体可以在体外产生并鉴定靶抗原。这创新方法最近已成功地应用于其他传染病，包括川崎我们的研究团队。通过分析CDI后的浆母细胞反应，我们将确定CDI后的浆母细胞反应。人抗体对C.艰难感染我们假设， C.艰难梭菌不限于毒素抗原，并且针对毒素和非毒素抗原两者的抗体提供抗艰难梭菌的抗体。保护CDI。具体来说，在这项可行性研究中，我们的目标是识别和克隆外周血 3例儿童和3例成人CDI后的浆母细胞反应，并鉴定C.艰难抗原靶点寡克隆后CDI浆母细胞使用各种蛋白质组学分析。在此可行性中获得的知识研究将为更大规模研究的设计提供信息，以验证C.更多样化的艰难抗原患者队列和这些抗体在不同的C.艰难菌株类型。在未来的研究，我们将确定抗体识别的特异性毒素和非毒素表位，自然CDI在人类中，我们将研究抗体如何响应C。艰难梭菌毒素和非毒素抗原影响C。难以定植和感染。广泛免疫原性抗原的鉴定将指导未来调查潜在的免疫候选人，以防止CDI和殖民化。我们的研究团队和西北大学的学术环境分别拥有以下技能和资源：成功完成拟定研究所必需的，包括患者队列的组装、细菌基因组学、浆母细胞分离、浆母细胞抗体合成和蛋白质组学。 !