Characterisation of Host and Viral Proteins Involved in the Innate Immune Response
Year: 2012
Type: dissertation
Abstract: The interplay between viral pathogens and the innate immune defences of vertebrates is complex, with advance by one side met with a countermeasure from the other. Understanding this exchange in molecular terms is essential to enable therapeutic advances, including the combat of viral disease, the neutralisation of viruses through vaccinology, and the manipulation of viruses for use in cancer therapy. This thesis reports the molecular investigation of proteins from each camp, contributing to a molecular understanding of host-virus interactions. On the side of the host, members of the IFN-induced, Mx protein family were investigated. Mx proteins play a key role in vertebrate defence against viruses, though the structural basis for their activity remains unclear. On the side of the virus, a virulence factor from Measles virus was investigated (the viral C protein). This modulator of the innate immune response is important for permitting efficient viral replication. However, the molecular mechanism remains unknown. Study of the Mx proteins initially involved analysis of protein assembly using structural and biophysical techniques. Subsequently, the N-terminal catalytic domain was investigated biochemically and biophysically. This study helped clarify how catalysis and Mx protein oligomerisation are linked, and established the deep similarities that exist with a related human protein, dynamin, that is involved in cellular vesicle endocytosis. Further detailed studies of this system will help develop a molecular model for Mx protein activity. Study of the measles C protein focused on structural characterisation, including biophysical investigation and attempts to determine the 3D structure using X-ray crystallography. A structured domain of Measles C was identified, which appears conserved in the Morbillivirus genus. Significant progress was made towards determining the structure and avenues for completing the structure determination were suggested. The structure may help us understand how the measles C protein antagonises the innate immune response.
Author: Siri A. McKelvie
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2337294502