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: 10400679
• 负责人: Christopher J Lyon
• 金额: $ 74.13万
• 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/10400679
• 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; Clinical/Radiologic; Cohort Studies; Collaborations; Data; Detection; Development; Devices; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic Sensitivity; Disease; Disease Progression; Disease model; 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; 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; 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; base; biomarker panel; co-infection; cohort; diagnostic assay; drug-sensitive; high risk; immune reconstitution; improved; latent infection; macrophage; mortality risk; multiplex assay; multiplex detection; mycobacterial; nonhuman primate; novel; pathogen; patient response; phenotypic biomarker; portability; predictive modeling; respiratory; response; simian human immunodeficiency virus; 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.

摘要