Evidence from animal models and from other Mycobacterial diseases in humans (e.g., leprosy) implicates a role for cytokine profiles in determining the outcome of human infection with Mycobacterium tuberculosis (M.tb.). These profiles are influenced in part by the host's ability to respond to infection, antigenic stimulation of the host, and underlying predisposing conditions. HIV infection is a major predisposing factor in TB and is epidemic in Zimbabwe. Iron overload has also been documented in Zimbabwe and evidence exists that iron plays a role in host response to M.tb. infection. Thus, the immune response to M.tb. infection is complex and is likely to be influenced by both genetic and environmental factors. Our ongoing study, """"""""Genetic Contribution of Host and Pathogen in African TB,"""""""" (AI 40019) examines variation at host immune response genes in M.tb. infected controls and TB cases, both with and without HIV co-infection. The current application will expand the ongoing study to allow dietary nutrients and cytokine responses to be tested, and it will permit a greater range of immune response genes to be examined. The sample of extrapulmonary TB (EPTB) cases will be augmented in an effort to understand the role of host genetic risk factors and cytokine responses in disease progression among infected individuals. We will address the following hypotheses: 1) Genetic variants that affect the expression or function of cytokines and iron metabolism will influence risk of TB; 2) Impaired IFN- and IL-12 responses occur in tuberculosis and are more profound when extrapulmonary or disseminated disease exists; 3) HIV-1 stage of infection can influence the type of cytokine response to M. tb. infection; and 4 ) Differences in iron status and iron metabolism influence risk of TB. To this end, we will recruit HIV+ and HIV- patients with PTB, HIV+ patients with EPTB (pleural effusion or lymphadenitis), or HIV+ and HIV- controls without TB who are PPD skin-test positive (n=125 per group, total n=750 subjects). These subjects will be screened for HLA class I and II genes, cytokine genes, and iron metabolism gene variation. Cytokine production in response to stimulation by mycobacterial antigens and markers affecting iron will be measured. HIV-1 infection will be staged by viral load and CD4 cell count. By understanding the role of host genetic variation, cytokine response, HIV infection, and iron in susceptibility to TB infection and disease progression, public health control measures can be pursued, including vaccine design, vaccine testing, cytokine therapy, and dietary recommendations.
