Wednesday, September 18, 2024
9/18/2024
DESCRIPTION (provided by applicant): The aim of these studies is to understand how the human protective immune response to tuberculosis (TB) is regulated. Our previous work suggests that the levels of inflammatory cytokines (TNF-a and IL-12) produced early in response to infection with M. tuberculosis determine the effectiveness of the Th1 response in the mouse. Clinical isolates of M. tuberculosis that fail to induce high IL-12 cause more severe disease (that is, are more virulent). In the mouse IFN-alpha/Beta (type 1 IFN) appear to downregulate the Th1 cytokine response. We hypothesize that in humans, M. tuberculosis clinical isolates that induce low levels of IL-12 and/or high levels of type 1 IFN in monocytes and dendritic cells (DC) will be more virulent, i.e., more likely to cause disease or more likely to cause severe manifestations of disease. In addition, we hypothesize that specific polyketides of M. tuberculosis are involved in induction of the differential cytokine response. To test these hypotheses we will ask the following questions: (1) Do specific M tuberculosis clinical isolates differentially induce IL-l2 in infected human monocytes/macrophages, thereby affecting the efficiency of the Th1 protective response? (2) Is the maturation and antigen presenting function of human myeloid dendritic cells (DC) differentially regulated by M. tuberculosis clinical isolates or by M. tuberculosis lipids? (3) Does IFN-a/b down regulate the development of IL-12 dependent Th1 responses in human TB? Do specific M. tuberculosis clinical isolates differentially induce IFN-a/b production by human leukocytes? To answer these questions we will examine the human leukocyte-M tuberculosis interaction in vitro using a combination of standard immunological assays (ELISA and lymphocyte proliferation; intracellular cytokine staining, FACS analysis), cell biologic assays (DC maturation) and molecular analyses of the monocyte response to infection (2-D gel electrophoresis with mass spectrometry.
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