Novel serological biomarker for rapid tuberculosis diagnosis

用于快速诊断结核病的新型血清学生物标志物

• 批准号: 8721846
• 负责人: Jacqueline Michele Achkar
• 金额: $ 17.86万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721846
• 关键词: Address; Antibodies; Antigens; Bacillus (bacterium); Bacteria; Bedside Testings; Biological Assay; Biological Markers; Categories; Data; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Early Diagnosis; Early treatment; Electrons; Enzyme-Linked Immunosorbent Assay; Exposure to; Gel; Genus Mycobacterium; Goals; Gold; Gram-Negative Bacteria; HIV; Health Priorities; Human; Image; Immune; Immune response; Immunoblotting; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; In Vitro; Infection; Integration Host Factors; Interferon Type II; Lead; Lung diseases; Mass Spectrum Analysis; Membrane; Methods; Microscope; Microscopy; Morbidity - disease rate; Mus; Mycobacterium bovis; Mycobacterium tuberculosis; Mycobacterium tuberculosis H37Rv; National Institute of Allergy and Infectious Disease; Patients; Pattern; Pneumonia; Population; Production; Proteins; Public Health; Pulmonary Tuberculosis; Recombinant Proteins; Recombinants; Resources; Scanning; Sensitivity and Specificity; Serologic tests; Serological; Serum; Spottings; Sputum; Staging; Strategic Planning; Testing; Tuberculin Test; Tuberculosis; Two-Dimensional Gel Electrophoresis; Vaccinated; Vesicle; Virulence; Virulence Factors; assay development; base; clinically relevant; communicable disease diagnosis; global health; healthy volunteer; immunogenicity; improved; innovation; mortality; mycobacterial; novel; nucleic acid detection; public health relevance; rapid diagnosis; response; sample collection; transmission process; two-dimensional; vector

DESCRIPTION (provided by applicant): Identification of easily detectable biomarkers for TB is a global health priority. With an estimated 8.8 million new cases of active tuberculosis (TB) occurring in 2010 TB remains a global public health problem. Rapid TB diagnosis is critical for early treatment initiation and reduction of transmission, morbidity, and mortality. Current rapid diagnostic tests lack either sensitivity (e.g. sputum microscopy) or cannot be easily applied in resource-limited settings (e.g., nucleic acid detection) where the vast majority of TB cases occur. Serum antibodies (Abs) can be rapidly detected by methods that can be turned into simple dip-stick formats. TB serology, however, has suffered from decades of unsuccessful attempts to develop accurate tests for TB. We have recently demonstrated that pathogenic mycobacteria produce membrane vesicles (MVs) that contribute to mycobacterial virulence in mice. These vesicles provide an effective way to release immune-modulatory factors and the host immune responses to MVs provide a unique opportunity for identification of novel biomarkers. Our preliminary data indicate that 3 proteins enriched in MVs of pathogenic mycobacteria induce a highly sensitive and specific Ab biomarker signature for TB. Therefore, our overarching hypothesis is that the simultaneous Ab response to specific MV proteins is strongly and significantly associated with TB. Consequently, we propose to use our well-characterized serum sample collection to develop these biomarkers for use in a rapid point-of-care (POC) test applicable in resource-limited settings. Our specific aims are: 1) To characterize Ab responses to mycobacterial MVs in patients suspected of having TB; and 2) To identify the mycobacterial MV proteins that elicit a TB Ab biomarker signature, express them in vitro, and verify Ab responses for diagnostic assay development. This is a highly feasible project with robust preliminary data and an innovative approach to address the need for a simple, rapid TB diagnostic. The ultimate goal of this proposal is the development of an assay that could lead to a POC test with the potential of replacing sputum microscopy for the diagnosis of TB.

描述(由申请人提供)：确定易于检测的结核病生物标志物是全球卫生优先事项。2010年估计有880万新的活动性结核病病例，结核病仍然是一个全球公共卫生问题。结核病的快速诊断对于及早开始治疗和减少传播、发病率和死亡率至关重要。目前的快速诊断测试要么缺乏敏感性(例如痰镜检)，要么不能轻易地应用于绝大多数结核病病例发生的资源有限的环境(例如核酸检测)。血清抗体(Abs)可以通过简单的试纸形式快速检测。然而，几十年来，结核病血清学一直在努力开发准确的结核病检测方法，但未获成功。我们最近证明，致病分枝杆菌产生膜泡(MVS)，有助于分枝杆菌对小鼠的毒力。这些囊泡提供了释放免疫调节因子的有效途径，而宿主对MVS的免疫反应为识别新的生物标志物提供了独特的机会。我们的初步数据表明，致病分枝杆菌MVS中富含的3种蛋白诱导出高度敏感和特异的结核抗体生物标志物特征。因此，我们的主要假设是，对特定MV蛋白的同时抗体反应与结核病密切相关。因此，我们建议使用我们特征良好的血清样本收集来开发这些生物标志物，用于适用于资源有限的环境中的快速护理点(POC)测试。我们的具体目标是：1)鉴定疑似肺结核患者对分枝杆菌MVS的抗体反应；2)鉴定引起结核抗体生物标记物特征的分枝杆菌MV蛋白，在体外表达它们，并验证抗体反应，用于诊断方法的建立。这是一个高度可行的项目，具有强大的初步数据和一种创新的方法，以满足对简单、快速的结核病诊断的需求。这项提议的最终目标是开发一种可能导致POC测试的测试方法，该测试有可能取代痰镜检用于诊断结核病。