Host Metabolic Biosignatures for the Diagnosis of Lyme Disease

用于诊断莱姆病的宿主代谢生物特征

基本信息

批准号：
10674095
负责人：
John T Belisle
金额：
$ 43.87万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-19 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10674095
关键词：
Address Adult Antibiotic Therapy Area Bacteria Biochemical Biological Biological Assay Biology Borrelia Borrelia burgdorferi Caring Centers for Disease Control and Prevention (U.S.)Childhood Classification Clinical Communicable Diseases Data Development Diagnostic Diagnostic Procedure Diagnostic tests Disease Early Diagnosis Europe Experimental Designs Funding Mechanisms Goals Immune response Individual Infection Ixodes Laboratories Laboratory Diagnosis Lyme Disease Lyme disease diagnosis Lyme disease diagnostic Mass Spectrum Analysis Medical Metabolic Metabolic Diseases Metabolic Pathway Methods Modeling Molecular Morbidity - disease rate National Institute of Allergy and Infectious Disease Pathway Analysis Pathway interactions Patients Population Population Control Publishing Reporting Research Research Activity Resolution Sampling Sensitivity and Specificity Serology Serology test Serum Source Southern Tick Associated Rash Illness Specificity Structure Symptoms Testing Therapeutic Intervention Ticks Uncertainty United States Vector-transmitted infectious disease antibody detection antibody test base biomarker discovery biosignature clinically relevant cohort detection test diagnosis standard diagnostic accuracy diagnostic assay diagnostic biomarker diagnostic tool disorder control erythema migrans high dimensionality implementation facilitation innovation mass spectrometer mathematical model metabolic profile metabolomics multiple reaction monitoring novel novel strategies potential biomarker prospective prospective test seropositive skin lesion small molecule tick bite tick transmission tick-borne tool

项目摘要

PROJECT SUMMARY Lyme disease is the most frequently reported vector-borne disease in the U.S., with 300,000 cases estimated to occur annually. Current diagnosis of Lyme disease is based on recognition of an erythema migrans (EM) skin lesion or positive two-tiered serological (antibody detection) testing in a patient with consistent clinical signs and tick exposure in areas where Lyme disease occurs. It is estimated that 20 to 30% of patients do not present with an EM, and the majority of patients do not recall a tick bite. Moreover, serologic tests are dependent on the host humoral immune response and lack sensitivity in early Lyme disease (only 29-40% of patients with EM are seropositive). Serological reactivity also may persist for years following antibiotic treatment and resolution of symptoms. These limitations and the need for early diagnosis to facilitate rapid therapeutic intervention provide strong rationale for the development of new Lyme disease diagnostic tests. We have undertaken a novel approach of applying serum metabolomics to develop small molecule biosignatures that can be exploited as a diagnostic test for early Lyme disease. These efforts resulted in a published candidate biosignature that provided a sensitivity of 88% for early Lyme disease with a specificity of 95% for healthy controls and 93% for other disease control populations. This approach was also able to differentiate early Lyme disease from Southern Tick Associated Rash Illness (STARI), an illness with an EM-like skin lesion and similar non-specific symptoms of early Lyme disease, and correctly classified these two patient groups with 98% accuracy for Lyme disease and 89% accuracy for STARI. Our preliminary data now provides strong evidence that metabolic profiles can differentiate early LD from other tick transmitted diseases and distinguish between the various manifestations of early Lyme disease (i.e., early localized versus early disseminated disease). Under this proposal, the expertise of biochemists, microbiologists, mathematicians, statisticians and infectious disease clinicians will be combined to perform studies that will significantly advance our previous efforts. Specifically, we hypothesize that it is possible to create a diagnostic metabolic profile that accurately distinguishes early Lyme disease patients from non-Lyme disease patients, and that can be applied in a clinical laboratory, Importantly the non-Lyme disease patient group are those individuals suspected of Lyme disease (patients who present for medical care and who undergo diagnostic testing for Lyme disease, but are not diagnosed with Lyme disease), as well as those with other tick transmitted diseases. Our proposed efforts take into account the heterogeneous symptoms of early Lyme disease and the non-Lyme disease populations. The goal of diagnostic development will be facilitated through the application of state-of-the-art mathematical modeling and well-characterized prospectively and retrospectively collected sera. Metabolites with the greatest discriminatory value for early Lyme disease will be structurally elucidated and characterized to facilitate implementation of a multianalyte multiple reaction monitoring assay as a platform for early Lyme disease diagnosis. Metabolic pathways associated with early Lyme disease will be elucidated to establish a biological rationale that support metabolic profiling as a diagnostic method for early Lyme disease.

项目概要莱姆病是美国最常报告的媒介传播疾病，估计有 300,000 例病例每年都会发生。目前莱姆病的诊断基于对游走性红斑 (EM) 皮肤的识别具有一致临床症状的患者出现病变或两级血清学（抗体检测）检测呈阳性接触莱姆病发生地区的蜱虫。据估计 20% 至 30% 的患者没有出现 EM，大多数患者不记得被蜱虫叮咬过。此外，血清学检测取决于宿主早期莱姆病的体液免疫反应和缺乏敏感性（只有 29-40% 的 EM 患者血清阳性）。在抗生素治疗和问题解决后，血清学反应也可能持续数年。症状。这些限制以及早期诊断以促进快速治疗干预的需要提供了开发新的莱姆病诊断测试的有力理由。我们承接了一部小说应用血清代谢组学开发小分子生物特征的方法，可用作早期莱姆病的诊断测试。这些努力产生了已发布的候选生物特征，该生物特征提供了对早期莱姆病的敏感性为 88%，对健康对照的特异性为 95%，对其他疾病的特异性为 93% 疾病控制人群。这种方法还能够区分早期莱姆病和南方蜱相关皮疹病 (STARI)，一种具有 EM 样皮肤病变和类似非特异性症状的疾病早期莱姆病，并正确分类这两个患者组，莱姆病的准确率达 98% STARI 的准确度为 89%。我们的初步数据现在提供了强有力的证据，表明代谢特征可以区分早期 LD 与其他蜱传播疾病，并区分 LD 的各种表现早期莱姆病（即早期局部疾病与早期播散性疾病）。根据该提案，生物化学家、微生物学家、数学家、统计学家和传染病的专业知识临床医生将联合起来进行研究，这将显着推进我们之前的努力。具体来说，我们假设有可能创建一个准确的诊断代谢谱区分早期莱姆病患者和非莱姆病患者，并且可以应用于临床实验室，重要的是，非莱姆病患者群体是那些疑似患有莱姆病的人疾病（前来就医并接受莱姆病诊断测试的患者，但未诊断出患有莱姆病），以及患有其他蜱传播疾病的人。我们建议的努力考虑到早期莱姆病和非莱姆病人群的异质症状。通过应用最先进的数学方法将促进诊断发展的目标建模并充分表征前瞻性和回顾性收集的血清。代谢率最高的早期莱姆病的歧视性价值将在结构上得到阐明和表征，以促进实施多分析物多重反应监测测定作为早期莱姆病的平台诊断。将阐明与早期莱姆病相关的代谢途径，以建立生物学机制支持代谢分析作为早期莱姆病的诊断方法的基本原理。