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Quantitative diagnosis of TB/HIV co-infection using pathogen-specific exosomes in blood

利用血液中病原体特异性外泌体定量诊断结核病/艾滋病毒合并感染

基本信息

批准号：
10021388
负责人：
Jia Fan
金额：
$ 7.58万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-25 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10021388
关键词：
Accounting Acute Address Affect Antibodies Antigens Automation Bioinformatics Biological Assay Biological Markers Biopsy Blood Blood Circulation Blood specimen Body Fluids Cells Cessation of life Characteristics Classification Clinical Communicable Diseases Data Analyses Detection Development Diagnosis Diagnostic Diagnostic tests Disease Disease Progression Early Diagnosis Early Intervention Effectiveness Endosomes Enzymes Exhibits Foundations Generations Goals HIV HIV Antibodies HIV Antigens HIV Core Protein p24 HIV Infections HIV Seropositivity HIV diagnosis HIV/TB Health Human Human immunodeficiency virus test Hydrolase Incidence Infection Intervention Machine Learning Malignant Neoplasms Masks Measures Mediating Minor Mycobacterium tuberculosis Nature Outcome Pathogenicity Patient-Focused Outcomes Patients Population Procedures Proteins Proteomics Reproducibility Sampling Sensitivity and Specificity Serum Signal Transduction Source Sputum Survival Rate T-Lymphocyte Testing Time Tuberculosis Validation World Health Organization base candidate marker co-infection cohort cost effective data acquisition diagnostic accuracy diagnostic assay disorder control exosome extracellular vesicles improved improved outcome innovation machine learning algorithm macrophage mortality nanoparticle novel novel diagnostics pancreatic neoplasm pathogen prevent protein biomarkers screening screening guidelines supervised learning

项目摘要

ABSTRACT Patients co-infected with HIV and tuberculosis (TB) exhibit accelerated progression of both diseases. A missed TB diagnosis in a HIV-positive patient, and vice versa, can have severe consequences, since mortality rates are very high in HIV/TB co-infected patients. The World Health Organization thus recommends HIV testing for TB patients and TB screening for HIV-affected patients. Early diagnosis of HIV/TB co-infections and appropriately timed interventions can improve health outcomes by slowing disease progression and reducing mortality and the spread of these infections. Given this urgent need for early diagnosis of HIV and TB, we propose to develop and validate a novel assay that rapidly and directly diagnoses both HIV and TB infections, using a sensitive nanoplasmon-enhanced scattering (nPES) platform to detect pathogen-specific (Ps) exosomes (PsExo) that carry TB- and/or HIV-derived antigens in patient serum samples. Ps antigens are often difficult to detect in circulation, due to low concentrations and potential masking by non-specific protein interactions or degradative enzymes, especially early in infection when antigen concentrations are low. Body fluids are rich in exosomes, and exosomes are rich sources of multiple Ps-antigens. Exosome enrichment effectively concentrates Ps- antigens and protects them from circulating hydrolases, thereby enhancing and improving detection. While use of PsExo as biomarkers for diagnosing specific infectious diseases is new and shows great promise, significant technical challenges, including the current lack of validated PxExo markers for specific diseases and simple and rapid assays for PsExo analysis, exist. We have recently demonstrated that we can use our nPES assay platform to quantify cancer-derived exosomes and diagnose early-stage pancreatic tumors from disease controls. We will adapt this approach to detect HIV and TB PsExo in this proposal. Aim 1 will address the first issue by identifying pathogenic proteins specifically or predominantly expressed on exosomes of infected cells and evaluating PsExo candidates by quantitative proteomics analysis of infected patients from Foundation for Innovative New Diagnostics (FIND) sample bank. Aim 2 will establish an optimized nPES array using Aim 1 PsExo biomarkers, apply machine learning to develop an nPES array that can effectively diagnose HIV, TB and HIV/TB patients based on nPES results, and validate these findings in an independent FIND cohort. This approach does not require a separate exosome isolation step and uses only microsample serum volumes. The proposed assay will benefit co-infected patients who are unable to produce sputum, extrapulmonary TB patients who often require invasive biopsies for diagnosis, and patients with acute HIV infections who are still HIV antibody negative.

摘要合并感染艾滋病毒和结核病（TB）的患者表现出两种疾病的加速进展。未接艾滋病毒阳性患者的结核病诊断，反之亦然，可能会产生严重的后果，因为死亡率在艾滋病毒/结核病合并感染患者中非常高因此，世界卫生组织建议对结核病进行艾滋病毒检测艾滋病毒感染者的结核病筛查。艾滋病毒/结核病合并感染的早期诊断，定时干预可以通过减缓疾病进展和降低死亡率来改善健康结果，这些感染的传播。鉴于对艾滋病毒和结核病早期诊断的迫切需要，我们建议制定和验证了一种新的检测方法，该方法可以快速直接诊断HIV和TB感染，使用敏感的纳米等离子体增强散射（nPES）平台检测病原体特异性（Ps）外泌体（PsExo），患者血清样本中携带结核病和/或艾滋病毒衍生抗原。Ps抗原通常很难检测到，循环，由于低浓度和非特异性蛋白质相互作用或降解的潜在掩蔽酶，特别是在感染早期，当抗原浓度低时。体液中富含外来体，外泌体是多种Ps抗原的丰富来源。外泌体富集有效地将Ps- 抗原，并保护它们免受循环水解酶的影响，从而增强和改善检测。虽然使用 PsExo作为诊断特定传染病的生物标志物是新的，技术挑战，包括目前缺乏针对特定疾病的经验证的PxExo标记物，以及简单和存在用于PsExo分析的快速测定。我们最近已经证明，我们可以使用我们的nPES检测平台，量化癌症来源的外泌体并诊断疾病对照的早期胰腺肿瘤。我们将在本提案中，采用这种方法来检测艾滋病毒和结核病PsExo。目标1将解决第一个问题，特异性或主要在感染细胞的外泌体上表达的致病蛋白，并评估PsExo 候选人通过定量蛋白质组学分析感染的患者从创新新基金会诊断（FIND）样本库。目标2将使用目标1 PsExo生物标志物建立优化的nPES阵列，应用机器学习开发一个nPES阵列，可以有效地诊断艾滋病毒，结核病和艾滋病毒/结核病患者基于nPES结果，并在独立的FIND队列中验证这些结果。这种方法不需要单独的外泌体分离步骤并且仅使用微量样品血清体积。拟定测定将有益于不能产生痰液的合并感染患者，肺外结核患者，用于诊断的侵入性活组织检查，以及HIV抗体阴性的急性HIV感染患者。