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）肺结核的高发病率和流行率，加上临床和实验室诊断基础设施的缺乏，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。与其他与艾滋病相关的机会性疾病不同，肺结核通常影响艾滋病患者的各个CD4+ T细胞层，这表明虽然CD4+ T细胞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有助于发病机制。在HIV感染期间，宿主氧化应激等代谢因子增加，这反过来可能降低宿主免疫反应，这在中和结核分枝杆菌（M. tb）方面最为有效。结核分枝杆菌的有效控制需要强大的“1型”免疫应答，这是由效应CD4+ T细胞谱定义的，该细胞谱分泌炎性细胞因子，如IFN-γ，进而可以激活肺巨噬细胞（M?），使其通过TNF-α和活性氮物种（RNIs）的活性变得更具杀菌和吞噬能力。

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.