PROgression of Tuberculosis infECTion in young children living with and without HIV: the PROTECT study

感染和未感染艾滋病毒的幼儿结核感染的进展：PROTECT 研究

• 批准号: 10641389
• 负责人: Adithya Cattamanchi
• 金额: $ 110.55万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641389
• 关键词: 5 year old; Acute; Address; Adolescent; Adult; Antibodies; Antibody Response; Antigen-Antibody Complex; Antigens; B-Lymphocytes; Bioinformatics; Biological; Biological Assay; Biological Markers; Blood Banks; Candidate Disease Gene; Cell Death; Cells; Cessation of life; Characteristics; Child; Childhood; Clinical; Country; Disease; Disease Progression; Early Diagnosis; Early treatment; Evaluation; Funding; Gambia; Gene Expression Profile; Genes; Genetic Transcription; Growth; HIV; Immune; Immunologic Sensitization; Immunologics; In Vitro; Infection; Injury; Link; Machine Learning; Mass Spectrum Analysis; Measures; Mouse Strains; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; National Institute of Allergy and Infectious Disease; Pathogenesis; Pathway Analysis; Pathway interactions; Performance; Phage ImmunoPrecipitation Sequencing; Plasma Cells; Predictive Value; Preventive therapy; Preventive treatment; Proteins; Proteome; Proteomics; RNA; Recommendation; Research; Resolution; Role; Sampling; Secondary to; South Africa; Specific qualifier value; Subgroup; System; Testing; Therapy trial; Tissues; Training; Translating; Tuberculosis; Tuberculosis diagnosis; Uganda; Urine; Vietnam; Viral Respiratory Tract Infection; Whole Blood; World Health Organization; biobank; bioinformatics pipeline; biomarker discovery; biomarker identification; biomarker panel; biomarker signature; biosignature; candidate identification; candidate marker; clinically relevant; cohort; diagnostic accuracy; field study; high risk; human model; immunopathology; in vivo; insight; ion mobility; metabolomics; mouse model; multiple omics; mycobacterial; next generation; novel; novel marker; point of care; point of care testing; response; scale up; segregation; targeted biomarker; tissue injury; tuberculosis immunity

PROJECT SUMMARY The vast majority of child tuberculosis (TB) deaths occur in children <5 years old, highlighting the importance of identifying young children at high risk of developing TB and initiating preventive treatment. However, current tests for Mycobacterium tuberculosis (Mtb) infection have poor predictive value for TB progression. To make progress toward biomarker-targeted TB preventive therapy in young children, there is an urgent need to identify novel host markers that reflect the unique pathogenesis of childhood TB, can be detected earlier in the course of disease progression and can be more easily translated to a point-of-care assay. The overall objective of the proposed project is to identify biomarker signatures among young children that meet the World Health Organization (WHO)-recommended minimum accuracy targets for a test of TB progression. We hypothesize that a subset of host biomarkers of childhood TB disease that reflect unsuccessful immune control of Mtb infection will have the best performance for early prediction of TB disease progression in young children. To examine our hypothesis, we propose to leverage 1) biorepositories that provide access to banked samples from children with presumptive TB and healthy children with and without TB exposure and Mtb infection (Uganda, South Africa, the Gambia); 2) biorepositories that provide serial samples from young children followed for 12 months or more for incident TB disease (Uganda, South Africa, Vietnam); and 3) state-of-the-art platforms and bioinformatic pipelines for multi-omics biomarker discovery. In Aim 1, we will measure and compare biomarker levels (host cell-free RNA, proteins, metabolites and antibodies to Mtb antigens) in symptomatic children with presumptive TB and healthy children to identify candidate host biomarkers that differentiate childhood TB disease, differentiate Mtb infection, overlap between TB disease and Mtb infection, and segregate Mtb infection into multiple sub-groups. In Aim 2, we will use pathway analysis, in vitro human models and in vivo mouse models to prioritize candidate host biomarkers that are functionally linked to immune control of Mtb infection. In Aim 3, we will derive biosignatures consisting of the prioritized candidate host biomarker(s) and evaluate their accuracy for predicting TB progression overall and among children living with HIV in independent training and test sets. Completion of these aims will result in identification of promising biosignatures that can be further validated in large-scale field studies and translated into point-of-care tests for predicting progression of childhood TB.

项目摘要 绝大多数儿童结核病（TB）死亡发生在5岁以下的儿童中，这突出了以下方面的重要性： 确定患结核病风险高的幼儿，并开始预防性治疗。但目前的 结核分枝杆菌（Mtb）感染的检测对结核病进展的预测价值很差。使 随着生物标志物靶向结核病预防性治疗在幼儿中的进展，迫切需要确定 反映儿童结核病独特发病机制的新型宿主标记物可在病程早期检测到 并且可以更容易地转化为即时检测。的总体目标 拟议的项目是确定符合世界卫生组织标准的幼儿生物标志物特征， 世界卫生组织（WHO）推荐的结核病进展检测的最低准确性目标。我们假设 反映Mtb感染免疫控制不成功的儿童结核病宿主生物标志物子集 将在早期预测幼儿结核病进展方面具有最佳性能。审视我们 假设，我们建议利用1）生物储存库，提供来自儿童的库存样本， 假定的结核病和健康儿童，有和没有结核病暴露和结核分枝杆菌感染（乌干达，南非， 冈比亚）; 2）生物储存库，提供来自幼儿的连续样品，随访12个月或更长时间， 突发结核病（乌干达、南非、越南）; 3）最先进的平台和生物信息学 多组学生物标志物发现的管道。在目标1中，我们将测量和比较生物标志物水平（宿主 无细胞RNA、蛋白质、代谢物和抗Mtb抗原抗体）在有症状的假定 结核病和健康儿童，以确定区分儿童结核病的候选宿主生物标志物， 区分Mtb感染，结核病和Mtb感染之间的重叠，并将Mtb感染分离为 多个子组。在目标2中，我们将使用通路分析、体外人类模型和体内小鼠模型 优先考虑与Mtb感染的免疫控制功能相关的候选宿主生物标志物。在目标3中， 我们将推导出由优先的候选宿主生物标志物组成的生物特征，并评估其准确性 在独立的培训和测试集中预测总体结核病进展以及艾滋病毒感染儿童的结核病进展。 这些目标的完成将导致确定有希望的生物特征，可以进一步验证， 大规模实地研究，并转化为用于预测儿童结核病进展的即时检测。