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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

基本信息

批准号：
10549285
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
项目类别：
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/10549285
关键词：
Antibodies Antibody Response B-Lymphocytes Binding 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 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 design gut inflammation individual patient infection management intestinal injury method development mortality neutralizing antibody novel novel vaccines outcome prediction predictive marker predictive test response tool

项目摘要

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.

摘要