Role of IL-17 in Protective Vaccine-induced Immune Responses Against Tuberculosis

项目总结

PROJECT SUMMARY Mycobacterium tuberculosis (Mtb) latently infects one-fourth of the world’s population, causing pulmonary tuberculosis (TB) in ~9 million people and resulting in ~1.3 million deaths each year1. The currently available TB vaccine, Mycobacterium bovis BCG (BCG), shows variable efficacy. In addition, Multi-Drug-Resistant (MDR) Mtb strains have recently emerged. Thus, there is a great need for new TB vaccines2. Studies in the past decade have mainly utilized induction of T helper cell type 1 (Th1) responses and the production of the cytokine, Interferon-gamma (IFNγ), as readout for vaccine efficacy against TB3. Our studies during the prior funding period demonstrated that Interleukin (IL)-17 and T helper type 17 (Th17) vaccine responses are critical for vaccine-induced immunity against TB4-6. Importantly, we recently demonstrated that mucosal vaccination with the Mtb antigen with Th17-inducing adjuvants induced potent lung-resident Th17 cells and improved BCG vaccine-induced protection following Mtb challenge4,6-8. Our mechanistic studies demonstrated that IL-17- induced chemokines, including CXCL-136,9-11, localize CXCR5-expressing T cells near Mtb-infected macrophages, resulting in the formation of lung lymphoid follicles and activating macrophages to mediate Mtb control5,12. Despite these major advances in understanding the role of Th17 vaccine-induced cells in TB, our data show that upon Mtb infection, the accumulation of vaccine-induced Th17 immune responses in the lung is not accelerated enough to provide “sterilizing” immunity or complete Mtb control5. In exciting new data generated during the prior funding cycle, we show that we can overcome this bottleneck by using Dendritic Cell (DC) based therapy by either activating endogenous DCs, or transfer of exogenously activated DCs into vaccinated hosts, to achieve superior Mtb control6,13. Thus, the work proposed in this R01 renewal builds on these important and highly relevant findings with three Specific Aims: Specific Aim 1. Identifying the early cytokine pathways that modulate APC function to promote Th17 responses and induce superior immunity against TB. Specific Aim 2. Identifying the IL-23 and IL-17-dependent mechanisms that mediate early Th17 responses and Mtb control. Specific Aim 3. Identification of novel C-type lectin receptor agonists as Th17- inducing TB vaccines. The emergence of extensively drug-resistant strains (XDR) of Mtb, for which no treatments currently exist, makes the development of an effective TB vaccine incredibly urgent. The work proposed in this grant will continue to significantly impact the design and use of future vaccine strategies by allowing us to promote IL-17 responses to generate improved, long-term lasting vaccine-induced immunity against TB.