Molecular determinants of IBDV pathogenesis and modulation of the host innate response

Abstract

Viruses are known to interact with the innate immune pathways and, in some cases, strains that differ in virulence are known to interact with these pathways in different ways. This thesis aimed to directly compare IBDV strains of differing virulence to determine key interactions with the innate immune response that may contribute to disease outcome. Infection of chicken B cells with the very virulent s UK661 strain, suppressed type I IFN responses compared to both infection with the cell-adapted IBDV strain, D78 in primary bursal cells, and infection with the classical strain, F52/70 in DT40 cells. Birds infected with UK661 also had down-regulated type I IFN and pro-inflammatory responses in the bursa of Fabricius (BF), compared to infection with F52/70. No difference in the peak virus titres was detected in the BF or spleen, although UK661 reached higher titres in the caecal tonsils than F52/70. Increased type I IFN production following F52/70 infection coincided with a reduced mortality in these birds, indicating a protective role of this immune response. The UK661 VP4 protein was found to suppress IFNβ production in vitro compared to the F52/70 VP4, which instead suppressed Mx1 production, indicating that the IBDV VP4 from different strains impairs either IFN production or signalling pathways. Upon knocking out the protease function of UK661 VP4, IFNβ production remained suppressed, and multiple amino acids are likely responsible for the different phenotype between strains. This work demonstrates that UK661 and F52/70 have strain-specific differences in their interactions with the innate immune response, mediated by the VP4 protein, therefore differences in this protein between strains may contribute to virulence. This information could be useful in the development of recombinant rationally designed live attenuated IBDV vaccines, by generating a vvIBDV backbone containing a VP4 from a classical or cell-adapted strain, as a vaccine candidate.