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Toll-Like Receptor Ligands as Antiviral Agents against Avian Influenza Viruses

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Title: Toll-Like Receptor Ligands as Antiviral Agents against Avian Influenza Viruses
Author: Barjesteh, Neda
Program: Pathobiology
Advisor: Sharif, Shayan
Abstract: Avian influenza viruses (AIV) are a significant threat to the poultry industry and public health. Recent outbreaks of AIV have provoked notable concerns about measures available for control of AIV. In conjunction with the research efforts focused on developing effective vaccines, there is a need to explore novel approaches to modulate host innate responses, as part of a strategy for rapid response against AIV outbreaks. The research presented here evaluated the antiviral activities of Toll-like receptor (TLR) ligands against AIV infection and assessed the underlying mechanisms of these activities. Initially, the potential ability of TLR ligands as antiviral agents against AIV was investigated using in vitro and in ovo models. Our results confirmed that TLR ligands were able to reduce AIV replication in chicken cells. However, different levels of antiviral activities were observed among TLR ligands. CpG ODN1826 caused the highest reduction in AIV replication in chicken macrophages and embryonated chicken eggs. Furthermore, results of the present research showed that TLR ligands were able to induce antiviral responses in chicken cells, as demonstrated by an increase in the expression of proinflammatory cytokines, type I interferons and some interferon-stimulated genes. Subsequently, several TLR ligands were examined in vivo to determine whether TLR ligands can reduce viral shedding from infected chickens. Our results demonstrated that all TLR ligand treatments reduced AIV shedding, with the CpG ODN1826 being the most efficacious to reduce oral virus shedding, whereas lipopolysaccharide (LPS) from Escherichia coli (E. coli) 026:B6 resulted in the largest reduction in cloacal virus shedding. To further explore the role of TLR ligands in inducing antiviral responses in the chicken respiratory system, tracheal organ cultures (TOC) were used to investigate localized innate responses to TLR ligands. The antiviral activity of TLR ligands in TOCs was demonstrated by induced expression of type I interferons (IFNs) and interferon-stimulated genes (ISGs) in TOCs and the reduction of AIV replication in treated TOCs. Overall, the results in this thesis identified candidate TLR ligands for control of AIV infection in chickens and also provided a better understanding of innate responses in chickens that contribute to protection against AIV.
Date: 2017-02-09

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