Mtb and HIV/SIV antigen peptide signatures as blood biomarkers to detect early infection to active disease in young children and NHP

Mtb 和 HIV/SIV 抗原肽特征作为血液生物标志物，用于检测幼儿和 NHP 中活动性疾病的早期感染

• 批准号: 10613462
• 负责人: Christopher J Lyon
• 金额: $ 73.16万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613462
• 关键词: Address; Adult; Antigens; Antitubercular Agents; Bacillus; Bacteriology; Biological Assay; Biological Markers; Blood; Breast Feeding; Bronchoalveolar Lavage Fluid; CD8-Positive T-Lymphocytes; Child; Childhood; Clinical; Cohort Studies; Collaborations; Data; Detection; Development; Devices; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic Sensitivity; Disease; Disease Progression; Disease model; Early Diagnosis; Enrollment; Evaluation; Exhibits; Exposure to; Funding; Goals; Guidelines; HIV; HIV Infections; HIV diagnosis; HIV/TB; Human; Immune; Immune response; Individual; Infant; Infection; Inflammatory; Life; Lung; Macrophage; Mass Spectrum Analysis; Measurement; Methods; Modeling; Monitor; Mucosal Immune Responses; Mycobacterium tuberculosis; Pathology; Patients; Pediatric cohort; Peptides; Performance; Persons; Population; Prediction of Response to Therapy; Proteomics; Radiology Specialty; Reaction; Reporting; Resistance; SIV; Sampling; Sensitivity and Specificity; Serum; Sputum; Symptoms; Syndrome; T-Lymphocyte Subsets; Testing; Time; Tissues; Translations; Treatment Efficacy; Treatment Failure; Tuberculosis; Tuberculosis diagnosis; Validation; Variant; Viral Antigens; Viral Load result; Virulence Factors; accurate diagnosis; biomarker identification; biomarker panel; co-infection; cohort; diagnostic assay; drug-sensitive; high risk; immune reconstitution; improved; latent infection; mortality risk; multiplex assay; multiplex detection; mycobacterial; nonhuman primate; novel; pathogen; patient response; phenotypic biomarker; portability; predictive modeling; respiratory; response; success; treatment response; tuberculosis diagnostics; tuberculosis treatment

ABSTRACT One million children develop TB annually; but current TB diagnostics exhibit poor performance in children, and the vast majority (96%) of the 205,000 children who die of TB-related causes each year do not receive treatment. Such children often present with non-specific symptoms and paucibacillary TB – particularly those co-infected with HIV – and are not diagnosed, and may then progress to disseminated or extrapulmonary TB cases that can rapidly progress in the absence of appropriate treatment. In young children, difficulty obtaining sputum samples used by most front-line TB diagnostics reduces the ability to accurately diagnose TB and monitor its response to treatment. Thus, non-sputum-based diagnostics are urgently needed to address this problem, but current versions of such assays either demonstrate poor sensitivity for active TB or cannot differentiate active disease from latent TB infection or accurately monitor treatment responses. We have reported that detection of virulence factors secreted by Mycobacterial tuberculosis (Mtb) in serum can diagnose all forms of TB in children (pulmonary and extrapulmonary TB), including paucibacillary and HIV- associated TB cases. We have recently shown that multiplex detection of HIV- and Mtb-derived protiens in serum can sensitively diagnose HIV and TB in young children, and simultaneously monitor their response to HIV and TB treatment. This is a critical issue for those at highest risk for mortality; very young children who may be exposed and/or infected with both pathogens while breastfeeding, during the first two years of life. Based on our success in identifying pathogen-specific peptide biomarkers and developing corresponding diagnostic assays, we propose to develop a multiplex HIV and TB assay for improved detection and monitoring of HIV viral load and all stages of TB, from early infection to active TB disease, in young children suspected HIV and TB infections or HIV/TB co-infections. We propose to achieve this goal through the pursuit of three interlinked specific aims where we will: 1) establish an assay for multiplex quantification of serum levels of TB-derived factors associated with each stage of TB development, from early infection to active TB disease in an infant non-human primate TB model that closely recapitulates the pathology of HIV and TB infection and co-infection; 2) develop a predictive model based on correlations between TB stage markers, immune responses and TB pathology in this disease model; and 3) conduct a multi-center validation of this multiplex assay to diagnose HIV infection and latent TB infections and early and active TB disease in HIV-exposed pediatric cohorts with carefully annotated clinical, radiological and bacteriological data. Employing a non-human primate model of HIV/TB co-infection and quantitative proteomics will allow us to identify TB-associated changes corresponding to symptom development and immune changes associated with disease progression that could not feasibly be detected using human cohorts. The comprehensive evaluation of our assay in multiple well-characterized pediatric cohorts will facillitate the rapid translation of these biomarkers into practice and the development of our portable device-based assay.

抽象的 每年有100万儿童发展TB；但是目前的结核病诊断暴露于儿童的表现不佳， 每年未接受与结核病相关的原因的205,000名儿童中，绝大多数（96％）没有收到 治疗。这样的孩子经常出现非特异性症状和paucibaCillarry结核病 - 尤其是那些 与HIV共同感染 - 未被诊断出来，然后可能进展到散布或肺外结核 在没有适当治疗的情况下可以快速进展的情况。在幼儿中，难以获得 大多数前线结核病诊断使用的痰液样本可降低准确诊断结核病和 监控其对治疗的反应。这是迫切需要基于非输出的诊断来解决这个问题 问题，但是当前的此类测定版本表明对活动结核的敏感性不佳或无法 将活动疾病与潜在结核病感染区分开或准确监测治疗反应。 我们报道了分枝杆菌结核（MTB）分泌的病毒因子的检测 可以诊断儿童（肺和肺外结核）中的所有形式的结核 相关的结核病病例。我们最近表明，串行中的HIV和MTB衍生的Protien的多重检测 可以敏感地诊断幼儿中的艾滋病毒和结核 结核病治疗。对于那些死亡率最高的人来说，这是一个关键问题。很小的孩子可能是 在生命的头两年中，母乳喂养时暴露和/或感染两种病原体。基于我们 成功识别病原体特异性肽生物标志物并开发相应的诊断测定法， 我们建议开发多重艾滋病毒和结核病分析，以改善对HIV病毒载荷的检测和监测 以及从早期感染到活跃结核病的所有阶段，在幼儿怀疑艾滋病毒和结核病感染中 或HIV/TB共同感染。我们建议通过追求三个相互联系的特定目标来实现这一目标 我们将在哪里：1）建立评估与结核病因素相关的血清水平的多重定量 随着TB发育的每个阶段，从早期感染到婴儿非人类灵长类动物TB的活性结核病 密切概括HIV和TB感染和共感染的病理的模型； 2）发展预测性 基于结核病阶段标记，免疫反应和TB病理学之间的相关模型 模型; 3）对此多重测定法进行多中心验证以诊断HIV感染和潜在TB 在艾滋病毒暴露的小儿同类群中感染和早期和活跃的结核病疾病，带有仔细注释的临床， 放射学和细菌数据。采用非人类的艾滋病毒/结核病联合感染的非人类私人模型和 定量蛋白质组学将使我们能够识别与SYM开发相对应的TB相关的变化 与疾病进展相关的免疫变化，使用人类无法可行地检测到 同伙。对我们在多个特征良好的小儿同伙中评估的全面评估将有助于 这些生物标志物的快速翻译成实践，以及我们基于便携式设备的测定法的开发。