Characterization of neutralizing antitoxins and epitopes in Clostridium difficile patients

艰难梭菌患者中和抗毒素和表位的特征

• 批准号: 10319522
• 负责人: Hanping Feng
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-16 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319522
• 关键词: Antibodies; Antibody Response; B-Lymphocytes; Binding; Biological Assay; Biological Markers; Cells; Characteristics; Clinical; Clostridium difficile; Data; Development; Diagnosis; Disease; Disease Outbreaks; Disease Outcome; Disease Progression; Enzyme-Linked Immunosorbent Assay; Epitopes; Financial cost; Frequencies; Future; Goals; Human; Immune; Immune response; Immunity; Immunodominant Epitopes; Immunoglobulin A; Immunoglobulin G; Immunoglobulin Isotypes; Individual; Infection; Kinetics; Knowledge; Lead; Maps; Mediating; Monoclonal Antibodies; Morbidity - disease rate; Outcome; Passive Immunotherapy; Patients; Prevention; Property; Recurrence; Serum; Severities; Severity of illness; Specificity; Testing; Therapeutic; Toxin; Vaccines; Virulence Factors; antitoxin; base; design; gut inflammation; individual patient; infection management; intestinal injury; method development; mortality; neutralizing antibody; novel; novel vaccines; outcome prediction; predictive marker; recurrent infection; response; tool

Abstract Intestinal injury and inflammation in Clostridium difficile infection (CDI), an increasing cause of morbidity, mortality and financial cost in the US, is mediated by two large clostridial toxins: TcdA & TcdB. Although antibodies against each toxin have been shown to be associated with protection, it is unclear what types of antibodies and their epitopes are responsible for effective immunity against CDI in patients. The goal of this project is to define the characteristics of a protective humoral immune response in CDI and the major neutralizing TcdA & TcdB epitopes. The hypothesis is that host antibodies directed against major neutralizing epitopes in TcdA & TcdB confer protection against CDI. To test this hypothesis, we will first validate our preliminary finding on neutralizing anti-TcdA/TcdB responses that correlate protection against severe CDI will also correlate protection against recurrence (Aim 1); subsequently we will characterize C. difficile toxin-specific B cell responses at clonal level and correlate these with CDI disease progression and recurrence (Aim 2); and finally we will clone neutralizing antibodies from individual B cells to obtain a representative panel of human protective monoclonal antibodies against the two toxins and characterize their binding epitopes and reactivity to a variety of toxins produced by major C. difficile endemic and outbreak strains (Aim 3). The completion of these specific aims can lead to the discovery of antibody biomarkers that predict outcomes of the most significant clinical issues in CDI management, including CDI occurrence, severity, and recurrence. Identification and characterization of protective antibodies may also facilitate the development of novel passive immunotherapy and vaccine approaches.

抽象的 艰难梭菌感染（CDI）的肠道损伤和炎症，这是发病率的越来越多的原因 美国的死亡率和财务成本是由两种大型梭菌毒素介导的：TCDA和TCDB。虽然 针对每种毒素的抗体已证明与保护有关，目前尚不清楚哪种类型的类型 抗体及其表位负责患者对CDI的有效免疫力。目标的目标 项目是定义CDI和主要的保护性体液免疫反应的特征 中和TCDA和TCDB表位。假设是针对主要中和的宿主抗体 TCDA和TCDB中的表位赋予CDI的保护。为了检验这一假设，我们将首先验证我们的 关于中和抗TCDA/TCDB响应的初步发现，将保护严重CDI的保护 还可以保护对复发的保护（AIM 1）；随后，我们将表征艰难梭菌特异性梭状芽胞杆菌 B细胞水平的B细胞反应，并将其与CDI疾病的进展和复发相关（AIM 2）；和 最后，我们将克隆中和来自单个B细胞的抗体以获得人类的代表性面板 针对两种毒素的保护性单克隆抗体，并表征其结合表位和反应性 由艰难梭菌流行和爆发菌株产生的多种毒素（AIM 3）。完成 这些具体目标可能导致发现最多预测结果的抗体生物标志物 CDI管理中的重大临床问题，包括CDI的发生，严重性和复发。 保护性抗体的识别和表征也可能有助于新型被动的发展 免疫疗法和疫苗方法。