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:
  • 金额:
    $ 7.58万
  • 依托单位:
  • 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

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), 在患者血清样品中携带TB和/或HIV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。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Cathepsin B Dependent Cleavage Product of Serum Amyloid A1 Identifies Patients with Chemotherapy-Related Cardiotoxicity.
血清淀粉样蛋白 A1 的组织蛋白酶 B 依赖性裂解产物可识别患有化疗相关心脏毒性的患者。
  • DOI:
    10.1021/acsptsci.9b00035
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Zhang,Fangfang;Lyon,ChristopherJ;Walls,RobertJ;Ning,Bo;Fan,Jia;Hu,TonyY
  • 通讯作者:
    Hu,TonyY
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Jia Fan其他文献

Jia Fan的其他文献

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{{ truncateString('Jia Fan', 18)}}的其他基金

Acquisition of next-generation Orbitrap Eclipse Tribrid Mass Spectrometer system
采购下一代 Orbitrap Eclipse Tribrid 质谱仪系统
  • 批准号:
    10431262
  • 财政年份:
    2022
  • 资助金额:
    $ 7.58万
  • 项目类别:
Adipose Tissue-Derived Extracellular Vesicles as Early Biomarkers of Type 2 Diabetes
脂肪组织来源的细胞外囊泡作为 2 型糖尿病的早期生物标志物
  • 批准号:
    10664054
  • 财政年份:
    2016
  • 资助金额:
    $ 7.58万
  • 项目类别:
Adipose Tissue-Derived Extracellular Vesicles as Early Biomarkers of Type 2 Diabetes
脂肪组织来源的细胞外囊泡作为 2 型糖尿病的早期生物标志物
  • 批准号:
    10504814
  • 财政年份:
    2016
  • 资助金额:
    $ 7.58万
  • 项目类别:

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