Eliciting Th1/Th17 dual responses for vaccine-induced immunity to tuberculosis - Abstract. The Bacillus Calmette-Guerin (BCG) vaccine has been in use for over a century and is currently administered in more than 200 countries to protect against tuberculosis (TB). Despite this, TB remains one of the leading causes of death due to an infectious disease. Efforts to improve or enhance BCG has been met with limited success in part due to the lack of an immune correlate that is associated with vaccine-induced protection in the human population. Although it is unclear why BCG remains ineffective against adult pulmonary TB, traditional animal models such as the C57BL/6 (B6) mice display a relatively homogenous Th1 response following BCG vaccination and fail to replicate the heterogeneous clinical response observed in human populations. Using the Collaborative Cross (CC) mice, we have demonstrated that host genetics is a critical determinant of both primary susceptibility and BCG-induced protection against Mtb, with the hope of using the CC model to identify immune signatures associated with protection that is not observed in the traditional B6 mice. Within several CC strains, we have identified a hybrid-Th1/17 population that is correlated with BCG-induced protection against Mtb, suggesting that this is a signal that is associated with vaccine- induced protection across multiple host genotypes. Using CC037, which is the strain that is the most protected against Mtb following BCG vaccination and has the strongest hybrid-Th1/17 signal, we will ask how BCG vaccination modifies host immunity in CC037 to generate this population in response to Mtb infection. As dendritic cells (DC) are considered the primary cell type that bridges the innate and adaptive immune systems, our overarching hypothesis is that modification of the DC compartment by BCG is leading to the generation of hybrid-Th1/17 response in CC037 mice. We will ask whether the ability to generate a hybrid-Th1/17 response is inherent to the host T cells or is due to certain signals produced by DC in response to BCG vaccination. We will also use a combination of scRNA-Seq and ATAC-Seq to examine how BCG modifies host T cell and DC responses to Mtb in CC037, from both a transcriptional and epigenetic approach. CC037 represents an important tool for understanding how hybrid-Th1/17 responses are generated and how they contribute to protective immunity against Mtb. This study aligns with the NIH NOT-AI-24-054, where we expect our study to identify novel mechanisms that will lead to the induction of this response and enhance TB vaccine development in the context of diverse genetic backgrounds.
