Quantitative Biomarkers for Loiasis

罗阿西病的定量生物标志物

• 批准号: 10415212
• 负责人: Philip Budge
• 金额: $ 19.69万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415212
• 关键词: Adverse event; African; Antigens; Area; Biological Assay; Biological Markers; Blood; Cameroon; Case Management; Cessation of life; Clinical; Collaborations; Coma; Detection; Development; Diagnosis; Diagnostic tests; Elephantiasis; Ensure; Filarial Elephantiases; Filariasis; Goals; Individual; Infection; Interruption; Ivermectin; Loa; Loa loa; Loiasis; Mass Spectrum Analysis; Measures; Metabolic Pathway; Metabolism; Microscopy; Monitor; Ocular Onchocerciasis; Onchocerciasis; Patients; Persons; Pharmaceutical Preparations; Plasma; Positioning Attribute; Proteins; Proteomics; Rapid diagnostics; Research; Resources; Sampling; Serious Adverse Event; Serum; Specificity; Test Result; Testing; Therapeutic; Tropical Disease; Universities; Washington; Work; antigen detection; base; biomarker discovery; candidate marker; candidate selection; clinical assay development; cross reactivity; detection assay; drug distribution; experience; experimental study; field study; improved; innovation; metabolic profile; metabolomics; predictive marker; prevent; programs; prospective; protein biomarkers; protein metabolite; success; tandem mass spectrometry; transmission process; treatment program; treatment response; treatment risk

PROJECT SUMMARY / ABSTRACT Significance. A quantitative antigen assay for loiasis is needed to diagnose active infection in non-endemic areas, to follow response to treatment, and to prevent severe adverse events by identifying and excluding from mass drug administrations individuals with heavy Loa loa infections (>20,000 microfilariae [Mf] per mL of blood). The goal of the work proposed here is to determine which circulating L. loa proteins adequately differentiate infected from uninfected individuals, and to define serum metabolic profiles that are associated with heavy L. loa microfilarial loads. Innovation. Prior attempts to develop quantitative antigen assays for loiasis have relied on targeted selection of candidate protein biomarkers based on their predicted specificity for L. loa and other factors felt to increase the chances of finding these candidates in infected plasma/serum. To date, these attempts have produced assays with inadequate sensitivity and poor to moderate correlation between the candidate biomarker and Mf loads. We propose an alternative approach that prioritizes detection of biomarkers with discriminatory capacity over predicted specificity. Using immunoaffinity purification and tandem mass spectrometry, we have previously detected over 200 L. loa proteins in plasma from one individual and one pooled plasma sample from patients with loiasis and falsely-positive rapid diagnostic tests for lymphatic filariasis (LF). We hypothesize that a subset these L. loa proteins found in cross-reactive sera are excreted/secreted by Mf and will therefore be present in sera from all loiasis patients in proportion to microfilarial loads. We further hypothesize that alteration in serum metabolite levels will correlate with the presence excreted/secreted filarial antigens, and will be more reliable than circulating filarial antigen levels at predicting total Mf load. We will test these hypotheses by defining the filarial antigen and metabolite profiles of banked plasma samples from 146 patients with L. loa Mf loads ranging from 8,000 – 114,000 Mf/mL and a matching number of amicrofilaremic endemic controls. Key to the success of this project is our access to 354 de-identified patient samples collected in collaboration with colleagues in Cameroon over the past 4 years. This will be the first application of metabolomic profiling to loiasis, and will be the most extensive proteomics analysis of loiasis samples to date. Impact. These studies will identify protein and metabolite biomarkers that correlate with L. loa infection intensity, and will identify metabolic processes that correlated with the presence of circulating Mf and filarial antigen in individuals with loiasis. This will provide promising candidates for the development of quantitative diagnostic tests for loiasis that can improve clinical case management and simplify test and not treat strategies for preventing loiasis-related adverse events during mass drug distributions for LF and onchocerciasis.

项目总结/摘要 意义在非地方性流行病中，需要对Loxyla进行定量抗原检测以诊断活动性感染。 通过识别和排除严重不良事件， 大量药物给药严重Loa loa感染（> 20，000微丝蚴[Mf]/mL血液）的个体。 本文提出的工作目标是确定哪种循环L。loa蛋白充分分化 从未感染的个体感染，并确定血清代谢谱，与重L。Loa 微丝蚴负荷 创新先前开发用于洛氏杆菌的定量抗原测定的尝试依赖于靶向选择洛氏杆菌的抗原。 候选蛋白质生物标志物基于它们对L. loa和其他因素认为， 在感染的血浆/血清中找到这些候选者的机会。到目前为止，这些尝试已经产生了测定 候选生物标志物和Mf载量之间的灵敏度不足且相关性差至中等。我们 提出一种替代方法，优先检测具有区分能力的生物标志物， 预测的特异性。使用免疫亲和纯化和串联质谱，我们以前 检测超过200 L。来自一个个体的血浆和来自患者的一个合并血浆样品中的loa蛋白 淋巴丝虫病（LF）的快速诊断试验呈假阳性。我们假设一个子集 这些L。在交叉反应性血清中发现的loa蛋白由Mf排泄/分泌，因此将存在于Mf中。 血清中的微丝蚴含量与微丝蚴载量成比例。我们进一步假设血清中的改变 代谢物水平将与排泄/分泌的丝虫抗原的存在相关，并且将更可靠 在预测总的Mf负荷方面，我们将通过定义 对146例丝虫病患者的血浆样本进行了丝虫抗原和代谢物谱分析。loa Mf载荷范围 8，000 - 114，000 Mf/mL和相应数量的无微丝蚴病地方病控制。成功的关键 该项目是我们与同事合作收集的354个去识别患者样本， 喀麦隆在过去的四年里。这将是代谢组学分析首次应用于Loxis， 迄今为止最广泛的蛋白质组学分析。 冲击这些研究将确定与L相关的蛋白质和代谢物生物标志物。感染强度， 并将确定与循环Mf和丝虫抗原存在相关的代谢过程， 个人love。这将为定量诊断的发展提供有前途的候选者 可以改善临床病例管理并简化测试而不是治疗策略的loxis测试 在LF和盘尾丝虫病的大规模药物分发过程中预防与Loiasis相关的不良事件。