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 万儿童患上结核病；但目前的结核病诊断方法在儿童中表现不佳， 每年死于结核病相关原因的 205,000 名儿童中，绝大多数 (96%) 没有得到治疗 此类儿童通常会出现非特异性症状和少杆菌性结核病，尤其是那些儿童。 合并感染艾滋病毒 - 未得到诊断，然后可能发展为播散性结核病或肺外结核病 如果没有适当的治疗，病例可能会迅速进展。 在幼儿中，难以获得。 大多数一线结核病诊断使用的痰样本降低了准确诊断结核病的能力 因此，迫切需要非痰诊断来解决这个问题。 问题，但此类检测的当前版本要么表现出对活动性结核病的敏感性较差，要么无法 区分活动性疾病和潜伏性结核感染或准确监测治疗反应。 我们报道了血清中结核分枝杆菌（Mtb）分泌的毒力因子的检测 可以诊断儿童所有形式的结核病（肺结核和肺外结核），包括少杆菌结核和艾滋病毒结核 我们最近证明了血清中 HIV 和 Mtb 衍生蛋白质的多重检测。 可以灵敏地诊断幼儿的艾滋病毒和结核病，并同时监测他们对艾滋病毒和结核病的反应 对于那些死亡率最高的儿童来说，结核病治疗是一个关键问题； 根据我们的数据，在母乳喂养期间接触和/或感染这两种病原体。 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， 我们建议开发一种多重 HIV 和 TB 检测方法，以改进 HIV 病毒载量的检测和监测 以及疑似艾滋病毒和结核病感染幼儿的所有结核病阶段，从早期感染到活动性结核病 我们建议通过追求三个相互关联的具体目标来实现这一目标。 我们将： 1) 建立一种对结核相关因子的血清水平进行多重定量的测定方法 结核病发展的各个阶段，从婴儿非人灵长类结核病的早期感染到活动性结核病 密切概括 HIV 和 TB 感染及合并感染病理学的模型 2) 开发预测模型； 基于结核病分期标记、免疫反应和结核病病理学之间相关性的模型 模型；3) 对这种多重检测进行多中心验证，以诊断 HIV 感染和潜伏性结核病 艾滋病毒暴露儿童群体中的感染和早期活动性结核病，并经过仔细注释的临床、 采用 HIV/TB 合并感染的非人类灵长类动物模型和 定量蛋白质组学将使我们能够识别与症状发展相对应的结核病相关变化 以及与疾病进展相关的免疫变化，而这些变化是人类无法检测到的 在多个特征明确的儿科队列中对我们的检测进行综合评估将有助于 这些生物标记物的快速转化为实践以及我们基于便携式设备的检测的开发。