The fusion (F) protein of Newcastle disease virus (NDV) is a type I membrane glycoprotein that mediates the merger of the viral envelope to the host cell membrane. The F protein activation initiates a series of conformational changes in the F protein leading to membrane merge which occurs at the cell surface at neutral pH thus modulating NDV entry and spread. The present studies have given an insight to understand the role of F protein in NDV pathogenesis by using established reverse genetic techniques. The F gene of NDV has six glycosylation sites, two of which are present in heptad repeats that facilitate conformational changes during fusion process. To understand the importance of the glycosylation sites in NDV replication and virulence, each site was eliminated individually and in combination on a cDNA clone of NDV strain BC. Our results suggest that glycosylation of F protein plays a major role in virulence and some of the N-glycosylation sites are critical for fusogenicity of the F protein thus modulating NDV infectivity.

The F protein is synthesized as an inactive precursor, F0, which is only

fusogenic after cleavage into disulfide-linked F1 and F2 polypeptides by host cell proteases. The amino acid sequence surrounding the F protein cleavage site determines the virulence of NDV, since different host proteases that cleave the F protein of virulent strains are present in more tissues than those that cleave the F protein of non-virulent strains. The role of conserved glutamine residue in NDV F protein cleavage site in viral pathogenesis has been examined. This study has helped us to understand the requirement of F protein cleavage site conserved amino acids in proteolytic processing and viral infectivity.

Further in this study, the role of F protein cytoplasmic domain and conserved cysteine residues in viral pathogenesis have been explored using reverse genetics. These regions have been suggested to play important roles in F protein conformation, stability and thus affecting the fusion process and viral infectivity.

In summary, the purpose of this work is to determine the important domains and residues of the NDV F protein that facilitates fusion process and regulates viral pathogenesis and immunogenicity. An understanding of how NDV F protein fusion process are regulated may lead to the creation of more effective therapies and better vaccine against NDV and other paramyxoviruses in general.