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

描述（由申请人提供）：撒哈拉以南非洲（SSA）肺结核发病率和患病率高，加上临床和实验室诊断基础设施缺乏，强调了在这一脆弱人群中验证预测疾病的生物标志物的重要性。与其他艾滋病相关的机会性疾病相比，肺结核通常影响不同CD 4 + T细胞层的艾滋病患者，这表明虽然CD 4 + T细胞绝对数量减少是疾病发展的风险因素，但其他宿主因素可能有助于发病机制。在HIV感染过程中，宿主代谢因子如氧化应激增加，这反过来可能降低宿主免疫应答，最有效地中和结核分枝杆菌（M. tb）。有效地控制了M.结核病需要强有力的“1型”免疫应答，其由分泌炎性细胞因子（如IFN-β）的效应CD 4 + T细胞谱定义，这反过来又可以激活肺巨噬细胞（M？）通过TNF-α和活性氮物质（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的患者中结核病的流行率和1年发病率。进行了增强的筛查措施（临床和实验室诊断：光学和荧光显微镜检查、胸部X线摄影和TB培养），并储存了血清标本，以实现我们在此概述的研究目标。我们的初步数据显示，在380名接受常规治疗的HIV患者中，69名患者（18.2%）在基线时有培养证实的肺结核，22名患者（5.8%）在随访时被诊断为结核病。结核病患者也更可能有胸部X线和肺部检查异常;他们也有较高的平均心率和呼吸率，但血压较低，CD 4计数中位数为201个细胞/uL。 鉴于这些观察结果，我们推测，慢性HIV疾病伴随的氧化应激增加可能会降低Th 1/Th 2细胞因子的比例，并可能随后破坏宿主控制结核病的免疫机制。这些假设将在以下特定目的的实验中得到解决：（1）确定HIV感染个体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”CD 4 + T辅助反应之间的关联;和（3）确定经典活化的“杀菌”巨噬细胞（caM？）或活化的“肉芽肿形成”巨噬细胞（aaM？）和艾滋病毒感染者中活动性结核病的发展。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，从而使人们能够更好地了解艾滋病毒感染患者的结核病随访和治疗时机。

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-?, that in turn can activate pulmonary macrophages (M?) to become more bactericidal and phagocytic through the activity of TNF-¿ 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 (caM?) or alternatively activated "granuloma-forming" macrophage (aaM?) 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.