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 由于结核病而受到影响，每年有200,000多人死亡。 HIV共感染已经 据估计，非洲儿童中有超过35％的结核病相关死亡导致了35％以上 艾滋病毒和结核病流行病的碰撞迄今为止最致命的。艾滋病毒感染以及 在艾滋病毒暴露但未感染的（heu）儿童中，子宫内的艾滋病毒暴露已与 幼儿中结核病发展的风险更高。无法预防结核病疾病和 破坏性归因于缺乏有效的疫苗以及我们无法 由于难以获得痰液，诊断5岁以下的儿童5岁 幼儿疾病的paucibacillary性质。因此，基于生物标志物的廉价 使用可用于在 在资源有限的设置中的护理点可以深刻改善结核病治疗和 防止儿童死亡，特别是在5岁以下的儿童中。而MTB特异性 由于无法 准确区分活性结核病与潜在结核病感染（LTBI），最近的数据 从我们的组中表明，MTB特异性抗体糖基化在跨越 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 跨地域跨地理的艾滋病毒感染状况的个人进入活跃和潜在疾病状态 甚至可以区分流行地区儿童最近的伤寒感染。基于 这些观察结果是一种简单的基于结合的测定，可以迅速，敏感地， 并明确检测来自小样品体积的MTB特异性抗体糖基化的变化 第一次提供机会开发抗原特异性抗体糖基化 从微层尺度样本中诊断为小儿结核病的诊断。鉴于艾滋病毒+，heu或 未暴露的儿童可能针对不同的MTB抗原，在这里我们组装了多学科 团队和程序称为更快的kids（儿童结核病的FC抗体特征） 那将：1）定义区分MTB特异性抗体糖基化反应的景观 结核病儿童，2）开发一个护理点测试，该测试将迅速捕获这些特定抗体 血液微量液的反应和糖基化变化。最终，这种合作 结构将使这种简单，快速，廉价的迭代改进和开发 诊断以管理幼儿的结核病感染。