Avian influenza virus has a segmented RNA genome that allows the virus to evolve continuously and generate new strains. Wild birds serve as natural reservoirs of avian influenza virus and provide a potential source for emergence of new viruses, which traverse host barriers and infect new avian or mammalian species. The mechanisms involved in this process are not completely understood. Our main goal is to understand host-pathogen interactions involved in avian influenza pathogenicity. As part of our approach we studied the effect of pre-exposure of chickens to IBDV (infectious bursal disease virus) on host susceptibility to infection, disease progression, and host molecular responses to infection with a mallard H5N2 low pathogenic avian influenza (LPAI) virus. We found that prior exposure of chickens to IBDV led to increased susceptibility to infection with the mallard H5N2 LPAI virus compared to normal chickens. This increased susceptibility allowed us to further adapt the virus to chickens. After 22 passages (P22) in IBDV-pre-exposed chickens, the LPAI virus replicated substantially better than the wild-type (WT) mallard virus in both IBDV-exposed and normal chickens. Interestingly, the P22 virus showed similar levels of replication in the respiratory and intestinal tracts of both groups, although it caused exacerbated signs of disease and severe lesions in the IBDV-pre-exposed group. We suggest that prior IBDV exposure provides a port of entry for avian influenza in an otherwise resistant chicken population. Furthermore, adaptation of avian influenza (AI) in IBDV-exposed chickens may allow for the selection of AI virus strains with expanded tissue tropism. We also studied the effects of host response to H5N2 AI in normal and IBDV-infected birds using high-throughput gene expression analysis. We demonstrated that IBDV-exposed chickens showed less than optimal humoral responses to LPAI infection as well as alterations in local molecular pathways that eventually led to exacerbated disease and death. At the molecular level we found amino acid substitutions in the surface glycoprotein hemagglutinin (HA). Those changes suggest selection for a virus that binds to and replicates more efficiently in chickens. Taken together our results suggest that IBDV-pre-exposure may play a role in exacerbating AI-induced pathogenicity.