Quantitative Biomarkers for Loiasis

罗阿西病的定量生物标志物

• 批准号: 10303430
• 负责人: Philip Budge
• 金额: $ 23.63万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303430
• 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; 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.

项目摘要/摘要