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

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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.