Oxidative stress and T cell balance: Effect on pulmonary tuberculosis during HIV

氧化应激和 T 细胞平衡：HIV 期间对肺结核的影响

基本信息

批准号：
8930464
负责人：
Lillian Seu
金额：
$ 5.68万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2016-08-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8930464
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Address Affect Africa South of the Sahara African Alabama Alveolar Macrophages Animal Disease Models Antioxidants Area Biological Markers CCL21 gene CD4 Lymphocyte Count CD4 Positive T Lymphocytes Caring Cause of Death Cell Count Cells Chest Chronic Clinic Clinical Cohort Studies Communicable Diseases Core Facility Coupled Data Development Diagnosis Diagnostic Disease Disease Progression Effector Cell Enrollment Equilibrium Fluorescence Microscopy Free Radicals Galectin 3 Gelatinase A Gelatinase B Generations Goals Granulocyte-Macrophage Colony-Stimulating Factor Granuloma HIV HIV Infections HIV Seropositivity Health Heart Rate Helper-Inducer T-Lymphocyte High Prevalence Hypotension Immune Immune response Immunologic Factors Immunology Incidence Individual Infectious Diseases Research Inflammation Inflammatory Integration Host Factors Interferon Type II Interleukin-10 Interleukin-13 Interleukin-4 Interstitial Collagenase Laboratories Lipid Peroxidation Lung Malondialdehyde Matrilysin Measurement Measures Metabolic Mono-S Mycobacterium tuberculosis Oxidative Stress Pathogenesis Patients Prevalence Pulmonary Tuberculosis Reactive Nitrogen Species Research Infrastructure Respiratory Burst Risk Risk Factors Serum Specimen T-Lymphocyte Testing Th1 Cells Th2 Cells Therapeutic Thoracic Radiography Time Tissues Training Tuberculosis Tumor Necrosis Factor-alpha Universities Vascular Endothelial Growth Factors Viral Vulnerable Populations Zambia bactericide blood pressure reduction burden of illness co-infection cohort cytokine follow-up global health high risk interleukin-12 subunit p40 killings light microscopy macrophage novel research study respiratory response routine care screening stromelysin 2 tuberculosis treatment

项目摘要

DESCRIPTION (provided by applicant): High levels of pulmonary tuberculosis incidence and prevalence, coupled with the paucity of clinical and laboratory diagnostic infrastructure in Sub-Saharan Africa (SSA) underscores the importance of validating biomarkers predictive of disease within this vulnerable population. In contrast to other AIDS-related opportunistic diseases, pulmonary tuberculosis typically affects AIDS patients at various CD4+ T cell strata, indicating that while diminished CD4+ T cell absolute numbers are a risk factor for the development of disease, other host factors may be contributing to pathogenesis. During HIV infection, host metabolic factors like oxidative stress are increased, and this in turn may reduce host immune responses most effective at neutralizing Mycobacterium tuberculosis (M. tb). Efficient control of M. tb requires a robust "Type 1" immune response that is defined by an effector CD4+ T cell profile that secretes inflammatory cytokines such as IFN-γ, that in turn can activate pulmonary macrophages (M?) to become more bactericidal and phagocytic through the activity of TNF-α and reactive nitrogen species (RNIs). The Centre for Infectious Disease Research in Zambia (CIDRZ) has recently concluded a longitudinal cohort study in Lusaka, Zambia, to determine both the prevalence and 1-year incidence of TB among patients seeking routine HIV care. Enhanced screening measures (clinical and laboratory diagnostics: light and fluorescence microscopy, chest radiography and TB culture) were performed, and serum specimens were also stored to pursue our study aims outlined here. Our preliminary data show that among the 380 enrolled HIV-patients seeking routine care, 69 patients (18.2%) had culture confirmed pulmonary TB at baseline, and 22 were (5.8%) diagnosed with incident TB at follow-up. Incident TB patients were also more likely to have chest x-ray and pulmonary exam abnormalities; they also had a higher mean heart rate and respiratory rate but lower blood pressure, and had a median CD4 count of 201 cells/uL. Given these observations, we hypothesize that the increased oxidative stress that accompanies chronic HIV disease may decrease the Th1/Th2 cytokine ratio, and may subsequently undermine host immune mechanisms to control TB disease. These hypotheses will be addressed in the experiments of the following Specific Aims: (1) to determine the association between oxidative stress and tuberculosis pathogenesis in HIV-infected individuals; (2) to determine the association between oxidative stress and a "Type 1" CD4+ T helper response; and (3) to determine the association between the classically activated "bactericidal" macrophage (caMɸ) or alternatively activated "granuloma-forming" macrophage (aaMɸ) and development of active tuberculosis among HIV-infected individuals. The results from this study will determine a biomarker for HIV patients at the highest risk for disease thereby allowing an enhanced understanding of the timing of follow up and treatment of TB in HIV infected patients.

描述（由申请人提供）：撒哈拉以南非洲 (SSA) 的肺结核发病率和患病率较高，加上临床和实验室诊断基础设施的缺乏，凸显了在这一弱势群体中验证预测疾病的生物标志物的重要性。与其他与 AIDS 相关的机会性疾病相比，肺结核通常影响不同 CD4+ T 细胞层的 AIDS 患者，这表明虽然 CD4+ T 细胞绝对数量减少是发展的危险因素在 HIV 感染过程中，氧化应激等宿主代谢因素会增加，这反过来可能会降低宿主的免疫反应，从而最有效地中和结核分枝杆菌 (M. tb)。结核病需要强大的“1 型”免疫反应，该反应由效应 CD4+ T 细胞特征定义，可分泌 IFN-γ 等炎性细胞因子，进而激活肺巨噬细胞(M?) 通过 TNF-α 和活性氮 (RNI) 的活性变得更具杀菌性和吞噬性。赞比亚传染病研究中心 (CIDRZ) 最近在赞比亚卢萨卡完成了一项纵向队列研究，以确定寻求常规艾滋病毒护理（临床和实验室诊断）的患者中结核病的患病率和一年发病率。：进行了光学和荧光显微镜检查、胸部X光检查和结核病培养），并且还保存了血清样本以实现此处概述的我们的研究目标。我们的初步数据显示，在 380 名受试者中。在寻求常规护理的 HIV 患者中，69 名患者（18.2%）在基线时患有培养证实的肺结核，22 名患者（5.8%）在随访时被诊断为突发结核病，突发结核病患者也更有可能进行胸部 X 光检查。和肺部检查异常；他们的平均心率和呼吸频率也较高，但血压较低，CD4 计数中位数为 201 个细胞/uL。鉴于这些观察结果，我们认为，伴随慢性 HIV 疾病的氧化应激增加可能会降低 Th1/Th2 细胞因子比率，并可能随后破坏控制结核病的宿主免疫机制。这些假设将在以下具体目标的实验中得到解决。：(1) 确定 HIV 感染者中氧化应激与结核病发病机制之间的关联；(2) 确定氧化应激与“1 型”CD4+ T 辅助细胞之间的关联； (3) 确定经典激活的“杀菌”巨噬细胞 (caMɸ) 或替代激活的“肉芽肿形成”巨噬细胞 (aaMɸ) 与 HIV 感染者中活动性结核病的发展之间的关系。确定疾病风险最高的 HIV 患者的生物标志物，从而加深对 HIV 感染患者的结核病随访和治疗时间的了解。