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abstract
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? DESCRIPTION (provided by applicant): Approximately one-third of the world's population is latently infected with Mycobacterium tuberculosis (Mtb) with a 10% risk of developing pulmonary tuberculosis (TB) over their lifetime. Global efforts to combat TB are hampered by the emergence of drug-resistant strains of Mtb and variable efficacy of the currently available vaccine, M. bovis BCG (BCG). Thus, the development of an effective vaccine is critical for the elimination of TB as a public health problem. Studies in the past decade have mainly utilized induction of T helper 1 (Th1) responses and production of interferon gamma (IFN?) as readouts for vaccine efficacy against TB. However, despite inducing high levels of IFN-?, MVA85A, the first recombinant TB vaccine tested in human clinical trials, failed to protect against TB disease. These data highlight the importance of exploring new approaches to improve vaccine-induced immunity against TB. During the prior funding period, we demonstrated that T helper type 17 (Th17) cells, which produce the cytokine interleukin-17 (IL-17), are the primary effector cell mediating vaccine-induced protection against Mtb. Although IFN? is dispensable for vaccine-induced immunity against TB, IL-17 production by vaccine-induced Th17 cells is absolutely necessary to confer vaccine-induced protection against TB. Importantly, mucosal vaccination with the Mtb antigen in adjuvant induced potent lung-resident Th17 cells and improved BCG vaccine-induced protection following Mtb challenge. Our mechanistic studies showed that IL-17 induced chemokines, including CXCL-13, to localize CXCR5-expressing T cells near Mtb-infected macrophages, resulting in the formation of lymphoid follicles and activating macrophages to mediate Mtb control. Despite these major advances in understanding the role of Th17 vaccine-induced cells in TB, the accumulation of vaccine-induced Th17 recall responses in the lung is not accelerated enough to provide sterilizing immunity to Mtb infection. However, we show that vaccine-induced Th17 immunity can be harnessed using DC therapy to achieve near sterilizing immunity against Mtb challenge. Thus, in this renewal, in Aim 1, we will first determine if accelerating Th17 cell accumulation by modulating antigen-presenting cell (APC) function will improve Mtb control. In Aim 2, we will address the functional role of IL-17 in DC therapy in vaccinated mice, and the relationship between a Single Nucleotide Polymorphism (SNP) in the IL-17 promoter and vaccine-induced responses in humans. Finally, in Aim 3, we will identify and incorporate potent Th17- inducing adjuvants into protective mucosal TB vaccines to translate for future use in humans. These objectives will be addressed using novel Mtb T-cell receptor (TCR) transgenic (Tg) mouse models in combination with gene-deficient mice, mouse models of Mtb infection, novel adjuvants and vaccination strategies, and hypothesis testing in humans. The work proposed in this grant will allow us to promote Th17 responses to generate long-lasting vaccine-induced immunity against TB.
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label
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ROLE OF IL-17 IN PROTECTIVE VACCINE-INDUCED IMMUNE RESPONSES AGAINST TUBERCULOSIS
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