Prevention of infectious diseases through vaccination remains a priority goal for scientists and public health officials. The high risk of developing multidrug-resistant Mycobacterium tuberculosis is a serious limitation to drug therapy, and consequently development of efficacious vaccines is critical for the successful eradication of tuberculosis. Vaccination against tuberculosis would rely on the immune system's ability to generate an appropriate protective response that can then be successfully garnered when the host is challenged with M. tuberculosis. Although we know that Th1 immunity is critical for protection against tuberculosis, yet the cells and mechanisms that are involved in generating a protective Th1 immunity are far from completely understood. In this proposal we combine two complementary approaches, a hypothesis-driven and low-through put approach and a global microarray analysis to ask mechanistic questions regarding how protective Th1 immunity to M. tuberculosis is generated. Therefore the central goal of this proposal is to examine the mechanism for the distinct cytokine response from dendritic cells and macrophages following M. tuberculois infection, and study its impact on the development of M. tuberculosis-reactive CD4 + Th1 cells in vivo: from naive to effector. Overall we expect to obtain from these studies an integrated appreciation of the dynamics of induction of Th1 immunity in tuberculosis. Successful completion of these studies will provide innovative strategies for vaccine development and also provide new modalities of modulating the immune response to shorten chemotherapy and/or overcome drug resistance.
The specific aims that will address the goals of the proposal are:
Aim 1. Corroborate the theory that signaling from TLRs is sufficient for IL-12 production from dendritic cells, and that macrophages require an additional signal to synergize with TLR signaling for IL-12 production.
Aim 2. Examine the molecular basis for differential IL-12 regulation in M.tuberculosis stimulated dendritic cells and macrophages.
Aim 3. Test the hypothesis that dendritic cells are critical for Th1 cell priming, and that macrophages are elemental for initiating the granulomatous response.
Aim 4. Compare the reprogramming of the dendritic cell and macrophage transcriptome in response to M.tuberculosis alone and in response to M.tuberculosis and interferon-gamma.
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