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Abstract
The vast majority of influenza studies focus on influenza A viruses (IAV); however, influenza B viruses (IBV) represent nearly one quarter of all influenza cases and are generally responsible for most cases late in the influenza season. The ferret is the gold standard animal model for influenza research in that it can readily be infected with influenza clinical samples, has similar course of disease, generate similar immune responses following infection and vaccination, and can transmit infectious virus to other ferrets and humans. Antibodies generated following infection of ferrets with human influenza viruses are used in surveillance to distinguish antigenic drift and cross-reactivity between vaccine viruses and circulating strains. IAVs generate robust antibody responses in ferrets, whereas IBVs require an additional booster dose over 85% of the time to generate equivalent antibody titers. This PhD investigates the disparity between IAV and IBV in ferret immune responses following infection and interventions to improve immune responses to IBV. Initial in vitro studies in primary, differentiated ferret nasal epithelial cell cultures reveal that delays in pro-inflammatory cytokines and interferons may play an important role in communication with other immune cells to allow for generation of robust antibody responses. Subsequent in vivo studies confirmed suppressed innate responses including reduced pro-inflammatory cytokines and interferons (IFN) in the serum. Compared to IAV infection, weak, delayed antibody levels were seen following IBV infection. The addition of adjuvanted ferret IFN was able to stimulate innate immune responses resulting in increased antibody levels in both IBV infected and vaccinated animals compared to untreated animals. These studies confirmed the low and delayed adaptive immune responses by IBV and provide further evidence that initial innate responses, especially IFN and proinflammatory responses play an important role in developing robust antibody responses. This work adds additional ferret immune reagents to aid in unraveling immune processes following infection with new and emerging respiratory viruses and the development of improved countermeasures quickly to address public health needs.