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

描述(申请人提供)：肺结核病发病率和患病率高，加上撒哈拉以南非洲(SSA)缺乏临床和实验室诊断基础设施，突显了在这一脆弱人群中验证预测疾病的生物标记物的重要性。与其他与艾滋病相关的机会性疾病不同，肺结核通常在不同的CD4+T细胞层影响艾滋病患者，这表明虽然CD4+T细胞绝对数减少是疾病发生的危险因素，但其他宿主因素可能在发病机制中起作用。在HIV感染期间，宿主代谢因素，如氧化应激增加，这反过来可能会降低宿主免疫反应，最有效地中和结核分枝杆菌(M.TB)。对结核分枝杆菌的有效控制需要强大的“1型”免疫反应，这种免疫反应是由一个效应的CD4+T细胞群决定的，它分泌炎性细胞因子，如干扰素-β，进而可以激活肺巨噬细胞(M？)。通过肿瘤坏死因子和活性氮(RNIs)的活性而变得更具杀菌力和吞噬能力。 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患病率和1年发病率。实施了加强筛查措施(临床和实验室诊断：光学和荧光显微镜、胸片和结核培养)，并保存了血清标本，以实现我们在这里概述的研究目标。我们的初步数据显示，在380名寻求常规治疗的登记的艾滋病毒患者中，69名患者(18.2%)在基线时有培养确认的肺结核病，22名患者(5.8%)在随访时被诊断为结核病。偶发结核病患者也更有可能有胸部X光和肺部检查异常；他们的平均心率和呼吸频率较高，但血压较低，CD4中位数为201个/ul。 鉴于这些观察结果，我们假设慢性HIV疾病伴随的氧化应激增加可能会降低Th1/Th2细胞因子比率，并可能随后破坏宿主控制结核病的免疫机制。这些假设将在以下特定目标的实验中得到解决：(1)确定氧化应激与HIV感染者结核病发病之间的关联；(2)确定氧化应激与“1型”CD4+T辅助反应之间的关联；(3)确定经典激活的“杀菌”巨噬细胞(CaM？)之间的关联。或者激活的“肉芽肿形成”巨噬细胞(AAM？)以及艾滋病毒感染者中活动性结核病的发展。这项研究的结果将为疾病风险最高的艾滋病毒患者确定一个生物标记物，从而使人们能够更好地了解艾滋病毒感染患者结核病的随访和治疗时间。

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.