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

• 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
• 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

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（由适用提供）：高水平的肺结核发生率和患病率，再加上撒哈拉以南非洲（SSA）临床和实验室诊断基础设施的匮乏强调了验证这种脆弱人群中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反，肺结核通常会影响各种CD4+ T细胞地层的艾滋病患者，表明虽然CD4+ T细胞的绝对数量减少是疾病发展的危险因素，但其他宿主因素可能导致病原体。在HIV感染期间，宿主代谢因子（如氧化应激）增加了，这又可以减少宿主免疫反应最有效地中和结核分枝杆菌（M. TB）。 M. TB的有效控制需要鲁棒的“ 1型”免疫反应，该免疫反应由效应子CD4+ T细胞谱定义，该疗效将诸如IFN-γ之类的炎症细胞因子（例如IFN-γ）构成，从而可以通过TNF-α和反应性NITRIS（RNIS）的活性来激活肺巨噬细胞（M？），以使肺巨噬细胞（M？）变得更加细菌和吞噬。 赞比亚（CIDRZ）的传染病研究中心最近在赞比亚卢萨卡（Lusaka）进行了一项纵向队列研究，以确定寻求常规HIV护理患者的结核病患者的患病率和1年发病率。进行了增强的筛查措施（临床和实验室诊断：光和荧光显微镜，胸部X射线照相和结核病培养），还存储了血清样本以追求此处概述的我们的研究目标。我们的初步数据表明，在寻求常规护理的380名招募的HIV患者中，有69名患者（18.2％）在基线时证实了培养证实的肺结核，而22例（5.8％）被诊断为随访时被诊断为入射TB。事件结核病患者也更有可能患有胸部X射线和肺部检查异常。他们的平均心率和呼吸速率也更高，但血压较低，并且中位CD4计数为201细胞/UL。 鉴于这些观察结果，我们假设涉及慢性HIV疾病的氧化应激增加可能会降低TH1/TH2细胞因子比率，并且随后可能破坏了控制结核病疾病的宿主免疫机制。这些假设将在以下特定目的的实验中解决：（1）确定HIV感染者中氧化应激与结核病发病机理之间的关联； （2）确定氧化应激与“ 1型” CD4+ T辅助响应之间的关联； （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感染的个体中活性结核病的发展。这项研究的结果将确定疾病风险最高的艾滋病毒患者的生物标志物，从而增强对以下时间的了解。在艾滋病毒感染患者中向上和治疗结核病。

项目成果

The host cell side of latent HIV-1 infection.

潜伏 HIV-1 感染的宿主细胞侧。

• DOI: 10.18632/oncotarget.5101
• 发表时间: 2015
• 期刊: Oncotarget
• 作者: Seu,Lillian;Kutsch,Olaf
• 通讯作者: Kutsch,Olaf