Host biomarkers for M. tuberculosis infection activity in HIV-infected persons

HIV 感染者中结核分枝杆菌感染活动的宿主生物标志物

• 批准号: 9115881
• 负责人: Jacqueline Michele Achkar
• 金额: $ 83.69万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-02 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9115881
• 关键词: Address; Antibodies; Antibody Response; Antigens; Biological Assay; Biological Markers; Body Fluids; Cause of Death; Cross-Sectional Studies; Data; Detection; Development; Diagnosis; Disease; Effectiveness; Evaluation; Goals; HIV; HIV Antigens; Human; Immune response; Immunoassay; Individual; Infection; Intervention; Lead; Life; Longitudinal Studies; Lung diseases; Mass Spectrum Analysis; Modeling; Molecular Profiling; Mycobacterium tuberculosis; Nucleic Acids; Patients; Persons; Population; Prevalence; Preventive therapy; Prospective Studies; Protein Array; Protein Microchips; Proteins; Proteome; Publishing; Reference Standards; Risk; Risk Factors; Sampling; Serum; South African; Techniques; Testing; Time; Tuberculosis; Validation; base; biomarker panel; co-infection; cohort; differential expression; disorder prevention; innovation; liquid chromatography mass spectrometry; multiple reaction monitoring; mycobacterial; novel; novel diagnostics; predictive modeling; prognostic; protein biomarkers; protein expression; prototype; public health relevance; response; screening; targeted treatment

 DESCRIPTION (provided by applicant): Reliable biomarkers to assess the activity level in Mycobacterium tuberculosis infection (Mtb) are urgently needed for targeted interventions towards the prevention of disease. This need is particularly high in the setting of HIV co-infection which is a major risk factor for active tuberculosis (TB) TB, the leading cause of death among people with HIV. Although latent Mtb infection (LTBI) and TB are commonly seen as binary states, reactivation and disease are preceded by a continuum of increasing infection activity within LTBI. In addition to being a strong risk factor for reactivation, HIV is also a ris factor for progression to TB due to exogeneous new or reinfection which is often rapidly progressive. The proposed studies seek to identify host protein and antibody (Ab) responses as correlates for Mtb infection activity in asymptomatic people living with HIV (PLHIV). Identificatio of such biomarkers could lead to the development of new diagnostics to predict the risk for reactivation in PLHIV, which could help optimizing the timing of preventive therapy initiation and may increase its effectiveness. Using liquid chromatography and mass spectrometry (LCMS), we have identified host proteins that are significantly differentially expressed in the sera of HIV individuals with TB compared to those with quiescent LTBI, or other respiratory diseases. Utilizing our novel Mtb protein microarray based on a unique nucleic acid programmable protein array (NAPPA) format that allows screening of sera for Abs to the entire Mtb proteome we have identified ~220 protein targets that are recognized by HIV+ TB patients but not those with quiescent LTBI. These preliminary data provide us with already identified selections of potential host biomarkers for further evaluation in our proposed studies. Our overarching hypothesis is that host protein and Ab profiles can constitute a biomarker for increasing Mtb infection activity and predict the risk for development of TB in PLHIV. Using novel innovative techniques, we propose to study prospectively collected stored samples from US and South African HIV+ cohort subjects up to two years pre and one year post development of TB (n=110), and compare them to those who have not developed TB. With these samples, we will address the following aims: Aim 1. Determine host protein biomarkers for increasing Mtb infection activity in PLHIV; Aim 2. Characterize Ab profiles associated with development of TB in PLHIV; and Aim 3. Develop prediction models for risk of TB in PLHIV. At the completion of the proposed studies we anticipate having identified single and/or multi-platform biomarkers as correlates for Mtb infection activity, and developed prototypes of targeted detection assays for further validation in large multi-center prospective studies.

 描述（由申请人提供）：为了预防疾病的有针对性的干预措施，迫切需要可靠的生物标志物来评估结核分枝杆菌感染（Mtb）的活性水平。在艾滋病毒合并感染的情况下，这一需求尤其高，艾滋病毒合并感染是活动性结核病 (TB) 的主要危险因素，而结核病是艾滋病毒感染者死亡的主要原因。尽管潜伏结核分枝杆菌感染 (LTBI) 和结核病通常被视为二元状态，但在 LTBI 内感染活动持续增加之前，再激活和疾病发生。 HIV 除了是重新激活的一个强烈危险因素之外，也是由于外源性新感染或再感染而进展为结核病的一个危险因素，而这种感染通常进展迅速。拟议的研究旨在确定宿主蛋白和抗体 (Ab) 反应与无症状艾滋病毒感染者 (PLHIV) 结核分枝杆菌感染活动的相关性。此类生物标志物的鉴定可能会导致新诊断方法的开发，以预测 PLHIV 重新激活的风险，这可能有助于优化预防性治疗开始的时机并可能提高其有效性。使用液相色谱和质谱 (LCMS)，我们鉴定出宿主蛋白在患有结核病的 HIV 个体与患有静态 LTBI 或其他呼吸道疾病的个体的血清中存在显着差异表达。利用我们基于独特的核酸可编程蛋白阵列 (NAPPA) 格式的新型 Mtb 蛋白微阵列，可以筛选血清中整个 Mtb 蛋白质组的抗体，我们已经确定了大约 220 个蛋白质靶点，这些靶点可以被 HIV+ 结核病患者识别，但不能被静态 LTBI 患者识别。这些初步数据为我们提供了已经确定的潜在宿主生物标志物的选择，以便在我们拟议的研究中进行进一步评估。我们的总体假设是，宿主蛋白和抗体谱可以构成增加 Mtb 感染活性的生物标志物，并预测 PLHIV 中发生结核病的风险。我们建议使用新颖的创新技术，对美国和南非 HIV+ 队列受试者在结核病发生前两年和一年后收集的前瞻性样本进行研究（n=110），并将其与未患结核病的受试者进行比较。通过这些样本，我们将实现以下目标： 目标 1. 确定宿主蛋白生物标志物，以增加 PLHIV 中 Mtb 感染活性；目标 2. 表征与 PLHIV 中发生结核病相关的抗体谱；目标 3. 开发 PLHIV 中结核病风险的预测模型。在完成拟议的研究后，我们预计已经确定了与 Mtb 感染活动相关的单一和/或多平台生物标志物，并开发了靶向检测分析的原型，以供进一步验证 大型多中心前瞻性研究。