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:
  • 金额:
    $ 7.84万
  • 依托单位:
  • 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

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。 !

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Translational Aspects of the Immunology of Clostridioides difficile Infection: Implications for Pediatric Populations.
艰难梭菌感染免疫学的转化方面:对儿童群体的影响。
Fidaxomicin for the treatment of Clostridioides difficile in children.
Fidaxomicin 用于治疗儿童艰难梭菌。
  • DOI:
    10.2217/fmb-2020-0104
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    3.1
  • 作者:
    Skinner,AndrewM;Scardina,Tonya;Kociolek,LarryK
  • 通讯作者:
    Kociolek,LarryK
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LARRY K KOCIOLEK其他文献

LARRY K KOCIOLEK的其他文献

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{{ truncateString('LARRY K KOCIOLEK', 18)}}的其他基金

Identification of the antigenic targets of the clonal antibody response to Clostridioides difficile infection
鉴定针对艰难梭菌感染的克隆抗体反应的抗原靶点
  • 批准号:
    10742376
  • 财政年份:
    2023
  • 资助金额:
    $ 7.84万
  • 项目类别:
Optimizing the diagnosis of pediatric Clostridium difficile infection
优化儿科艰难梭菌感染的诊断
  • 批准号:
    9087683
  • 财政年份:
    2016
  • 资助金额:
    $ 7.84万
  • 项目类别:
Optimizing the diagnosis of pediatric Clostridium difficile infection
优化儿科艰难梭菌感染的诊断
  • 批准号:
    9220710
  • 财政年份:
    2016
  • 资助金额:
    $ 7.84万
  • 项目类别:

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