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

基本信息

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
项目类别：
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

项目摘要

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岁的儿童中，强调了重要性确定患有结核病和启动预防治疗的高风险的幼儿。但是，当前结核分枝杆菌（MTB）感染的测试对于结核病进展的预测价值较差。做在幼儿中，以生物标志物为靶向生物标志物的结核病预防疗法，迫切需要识别可以在课程的早期检测到反映儿童结核病独特发病机理的新型宿主标记疾病进展，可以更容易地翻译成护理点测定。总体目标拟议的项目是确定符合世界卫生的幼儿的生物标志物签名组织（WHO）（WHO）强调了最低准确性目标，以测试结核病进展。我们假设这一点儿童结核病疾病的宿主生物标志物的子集，反映了MTB感染的免疫控制失败对于早期预测幼儿结核病疾病进展的表现最好。检查我们的假设，我们建议利用1）生物库，可从推定的结核病和健康的儿童，有和没有结核病暴露和MTB感染（乌干达，南非，冈比亚）; 2）提供来自幼儿的串行样本的生物库，紧随其后的12个月或更长时间事件结核病病（乌干达，南非，越南）； 3）最先进的平台和生物信息学多派生物标志物发现的管道。在AIM 1中，我们将测量和比较生物标志物水平（主机有症状儿童的无细胞RNA，蛋白质，代谢产物和MTB抗原的抗体结核病和健康儿童以识别有区别儿童结核病疾病的候选生物标志物，区分MTB感染，TB疾病和MTB感染之间的重叠，并将MTB感染分离为多个子组。在AIM 2中，我们将使用途径分析，体外人类模型和体内小鼠模型优先考虑与MTB感染的免疫控制在功能上相关的候选宿主生物标志物。在AIM 3中，我们将得出由优先候选宿主生物标志物组成的生物签名并评估其准确性用于预测总体上的结核病进展以及在独立培训和测试集中艾滋病毒携带的儿童中。这些目标的完成将导致确定有希望的生物签名，可以进一步验证大规模现场研究，并转化为预测儿童结核病进展的护理点测试。