Project 4: The intersection of innate and adaptive immunity to M. tuberculosis

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Project Summary/Abstract (Project 4, Stanley) Infection with Mycobacterium tuberculosis continues to be a leading cause of death worldwide. Efforts to combat the tuberculosis pandemic are hampered by the lack of an effective vaccine. Vaccines against Mtb and other intracellular pathogens that require cell-based immunity for control have been difficult to develop, in part due to the limited number of adjuvants that elicit effective cell-based immunity. We recently reported that that STING-activating cyclic dinucleotides (CDNs) formulated in a protein subunit vaccine elicit long-lasting protective immunity to Mycobacterium tuberculosis in the mouse model. The efficacy of CDN adjuvanted vaccines is dramatically improved when the vaccine is delivered via a mucosal route. Here we propose to perform an in-depth characterization of the immune response to CDN adjuvanted protein subunit vaccines for tuberculosis. First, we will determine how STING activation results in the development of protective immunity, using knockout mice to dissect the contribution of the different outputs of STING signaling. Second, we have found that the efficacy of vaccination with CDN is dependent on IL-17, however the mechanisms underlying the protective efficacy of IL-17 are unknown. We will determine how IL-17 impacts the vaccine elicited immune response, which CD4 Th17 subsets are most important, and which cell types in the lung respond to IL-17. Finally, we test CDN adjuvanted protein subunit vaccines in heterologous prime boost regimens designed to elicit complementary immune responses using recombinant BCG and Listeria monocytogenes strains developed by the Cox (Project 2) and Portnoy (Project 1) labs. If successful, this project will uncover novel mechanisms by which vaccines can elicit protective immunity to TB, and will exploit this knowledge to identify vaccination regimens with enhanced efficacy.