The host factors and mechanisms involved in the pathogenesis of pulmonary tuberculosis in the setting of AIDS as well as in the normal host are poorly understood. The long term objective of this project is to further identify and to characterize host factors that predispose individuals to develop pulmonary tuberculosis. Preliminary data indicate an association of an HLA allele, the HLA-DQB1*0503 class II allele, with susceptibility to pulmonary tuberculosis in Cambodia.
Specific Aim 1 will determine whether the same or different HLA alleles are associated with TB progression in a genetically distinct population from South Africa. The TNF-alpha gene occurs in the class III region of the major histocompatibility complex (MHC) and its protein product plays a critical role in the containment of tuberculosis infection. Studies will include the identification of polymorphisms and microsatellites in the tumor necrosis factor-alpha (TNF-alpha) gene, and their association to tuberculosis susceptibility.
Specific Aim 2 will characterize the mechanisms of activation of the TNF-alpha gene by mycobacteria. By using the TNF-alpha gene promoter as a target, these studies could define the molecular mechanisms of the activation of this important gene by mycobacteria.
Specific Aim 3 proposes to investigate the genetic and molecular determinants of anergy in the setting of pulmonary tuberculosis.
This aim will investigate whether there is an HLA association with anergy or lack of DTH, and will characterize the cytokine profiles and T cell proliferative responses in anergic pulmonary tuberculosis patients.
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