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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI054361-01
Application #
6596752
Study Section
Special Emphasis Panel (ZRG1-BM-1 (01))
Program Officer
Sizemore, Christine F
Project Start
2002-09-15
Project End
2007-06-30
Budget Start
2002-09-15
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$296,111
Indirect Cost
Name
Public Health Research Institute
Department
Type
DUNS #
City
Newark
State
NJ
Country
United States
Zip Code
07103
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Middelkoop, Keren; Bekker, Linda-Gail; Mathema, Barun et al. (2014) Factors affecting tuberculosis strain success over 10 years in a high TB- and HIV-burdened community. Int J Epidemiol 43:1114-22
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Middelkoop, Keren; Bekker, Linda-Gail; Mathema, Barun et al. (2009) Molecular epidemiology of Mycobacterium tuberculosis in a South African community with high HIV prevalence. J Infect Dis 200:1207-11
Mansoor, Nazma; Scriba, Thomas J; de Kock, Marwou et al. (2009) HIV-1 infection in infants severely impairs the immune response induced by Bacille Calmette-Guérin vaccine. J Infect Dis 199:982-90
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Bochud, P-Y; Sinsimer, D; Aderem, A et al. (2009) Polymorphisms in Toll-like receptor 4 (TLR4) are associated with protection against leprosy. Eur J Clin Microbiol Infect Dis 28:1055-65
Kana, Bavesh D; Gordhan, Bhavna G; Downing, Katrina J et al. (2008) The resuscitation-promoting factors of Mycobacterium tuberculosis are required for virulence and resuscitation from dormancy but are collectively dispensable for growth in vitro. Mol Microbiol 67:672-84

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