| The immunobiology of respiratory virus infection is complex, and immunity depends upon the successful integration of contributions from the innate, humoral, and cell-mediated branches of the immune system. This dissertation focuses on cell-mediated immunity to respiratory viruses, and was motivated by 3 main questions 1) how and under what circumstances can the novel vaccine adjuvant AdjuplexRTM generate CD8 T-cell responses to non-replicating antigens, 2) what are the key gaps in our knowledge of anti-viral CD4 T-cell memory, and 3) can a systems biology analysis be used to elucidate the complex biology of ferret host responses to pandemic influenza viruses. We found that the vaccine adjuvant AdjuplexRTM can elicit potent CD8+ T-cell responses to non-replicating antigens in mice, and can be administered by multiple routes. We also found that systemic and intranasal vaccinations with AdjuplexRTM generate similar CD8+ T-cell recall responses in the lung after influenza challenge. However, only intranasal vaccines are protective, and protection correlates with increased effector and resident memory populations in the lung. Importantly, intranasal vaccination also results in potent heterosubtypic immunity. Mechanistically, AdjuplexRTM functions through complex interactions with innate cells in vivo and in vitro, including alterations in recruitment and activation of antigen-presenting cells, as well as antigen up-take and processing. Next, we identified important functionally distinct subsets of CD4 T cells that differ in their phenotype, trafficking patterns, and intrinsic abilities to differentiate into memory cells, and proposed a new integrated model for understanding CD4 T-cell memory generation that accounts for phenotypic plasticity. Lastly, we characterized and validated a complex systems-biology approach to analyzing host immune responses to infection with influenza, and in doing so identified new associations between histologic lesions, virus subtypes, gene expression patterns, and changes in abundance of lipids, metabolites, and proteins during the course of infection. This research provides critical insights into the mechanisms by which vaccine adjuvants can be used to generate protective CD8 T-cell immunity to non-replicating antigens, outlines a new model for understanding CD4 T cell memory generation, and validates the use of systems biology approaches to gain critical insights into the complex host responses to influenza virus infection. |
