Multiplexed Antigen-Specific Antibody Fc Profiling on a Chip for Point-of-Care Diagnosis of TB in HIV-infected Children

芯片上的多重抗原特异性抗体 Fc 分析用于 HIV 感染儿童结核病的护理点诊断

• 批准号: 10159844
• 负责人: Galit Alter
• 金额: $ 96.06万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-06 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10159844
• 关键词: 5 year old; Acute; Adult; Affect; Africa; Age; Antibodies; Antibody Response; Antibody titer measurement; Antigen Targeting; Antigens; Area; Binding; Biological Assay; Biological Markers; Blood; Cause of Death; Cessation of life; Child; Childhood; Classification; Clinical; Data; Detection; Development; Devices; Diagnosis; Diagnostic; Diagnostic tests; Disease; Drops; Electrical Engineering; Enrollment; Epidemic; Exposure to; Failure; Geography; Goals; HIV; HIV Infections; HIV/TB; Immunologist; Individual; Infant; Infection; Inflammatory; Link; Machine Learning; Measurement; Measures; Mycobacterium tuberculosis; Nature; Polysaccharides; Population; Preparation; Pulmonary Tuberculosis; Reporting; Resources; Sampling; Scheme; Sensitivity and Specificity; Serology test; Serum; Severities; South Africa; Specificity; Sputum; Structure; System; Technology; Testing; Time; Translating; Tuberculosis; Typhoid Fever; Vaccines; base; biomarker signature; co-infection; cohort; diagnostic accuracy; glycosylation; high risk; improved; microchip; miniaturize; multidisciplinary; novel; pathogen; pediatrician; point of care; point of care testing; point-of-care detection; point-of-care diagnosis; point-of-care diagnostics; prenatal exposure; prevent; programs; prospective; response; sensor; tuberculosis treatment

Abstract: Tuberculosis (TB) is a leading cause of death in children, with an estimated 1 million children affected, and more than 200,000 deaths in children yearly due to TB. HIV coinfection has been estimated to contribute to more than 35% of TB-related deaths in children in Africa, making the collision of the HIV and TB epidemics one of the most lethal to date. Both HIV infection as well as HIV-exposure in utero, among HIV-exposed but uninfected (HEU) children, have been linked to higher risks for the development of TB among young children. Failures to prevent TB disease and devastation has been attributed to the lack of an effective vaccine as well as our inability to diagnose children under the age of 5 due to the difficulty in obtaining sputum and the paucibacillary nature of the disease in young children. Thus, an inexpensive biomarker-based diagnostic test tailored for pediatric TB using non-sputum samples that could be used at the point of care in resource-limited settings could profoundly improve TB treatment and prevent deaths in children, especially in those under 5 years of age. While Mtb-specific antibody titer-based diagnostics have performed poorly in the past, due to the inability of accurately distinguishing between active TB disease from latent TB infection (LTBI), recent data from our group has shown that Mtb-specific antibody glycosylation shifts significantly across disease states. Moreover, this antigen-specific antibody glycosylation approach reliably classifies individuals into active and latent disease states across HIV infection status, across geographies and can even distinguish recent Typhoid infection among children in endemic areas. Based on these observations, a simple binding-based assay was developed that can rapidly, sensitively, and specifically detect changes in Mtb-specific antibody glycosylation from a small sample volume offering an opportunity for the first time to develop an antigen-specific antibody glycosylation diagnostic for pediatric TB from a microliter-scale sample. Given that HIV+, HEU, or unexposed children may target distinct Mtb antigens, here we have assembled a multi-disciplinary team and program termed FASTER-Kids (Fc Antibody Signatures for TubERculosis in children) that will: 1) Define the landscape of Mtb-specific antibody glycosylation responses that distinguish children with TB, 2) Develop a point-of-care test that will rapidly capture these specific antibody responses and glycosylation changes from microliters of blood. Ultimately, this collaborative structure will enable the iterative improvement and development of this simple, rapid, inexpensive diagnostic to manage TB infection in young children.

抽象的： 结核病 (TB) 是儿童死亡的主要原因，估计有 100 万儿童患有结核病 每年有超过 200,000 名儿童死于结核病。 HIV合并感染已 据估计，非洲儿童 35% 以上的结核病相关死亡是由结核病造成的，这使得 艾滋病毒和结核病流行病的碰撞是迄今为止最致命的流行病之一。无论是HIV感染还是 暴露于艾滋病毒但未感染的 (HEU) 儿童中，子宫内艾滋病毒暴露与 幼儿患结核病的风险更高。未能预防结核病和 造成破坏的原因是缺乏有效的疫苗以及我们无法 诊断5岁以下儿童，由于痰液获取困难，且 幼儿中该疾病的细菌性很少。因此，一种廉价的基于生物标记的 使用非痰样本为儿童结核病量身定制的诊断测试，可用于 在资源有限的环境中进行护理可以极大地改善结核病治疗 预防儿童死亡，特别是 5 岁以下儿童。虽然 Mtb 特定 基于抗体滴度的诊断过去表现不佳，因为无法 准确地区分活动性结核病与潜伏性结核感染 (LTBI)，最新数据 我们小组的研究表明，Mtb 特异性抗体糖基化在不同时期发生显着变化 疾病状态。此外，这种抗原特异性抗体糖基化方法可靠地分类 跨地区、跨艾滋病毒感染状态的个体进入活跃和潜在疾病状态 甚至可以区分流行地区儿童中最近感染的伤寒。基于 根据这些观察结果，开发了一种简单的基于结合的测定法，可以快速、灵敏地 并从少量样品中特异性检测 Mtb 特异性抗体糖基化的变化 首次提供了开发抗原特异性抗体糖基化的机会 从微升样本中诊断儿童结核病。鉴于 HIV+、HEU 或 未接触过的儿童可能针对不同的 Mtb 抗原，在这里我们汇集了多学科的 名为 FASTER-Kids（儿童结核病 Fc 抗体特征）的团队和项目 这将： 1) 定义区分 Mtb 特异性抗体糖基化反应的情况 患有结核病的儿童，2) 开发一种能够快速捕获这些特异性抗体的即时检测 微升血液的反应和糖基化变化。最终，这次合作 结构将使这种简单、快速、廉价的迭代改进和开发成为可能 诊断以控制幼儿结核感染。