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Title: Towards defining the cellular and molecular function of the broad-spectrum antiviral IFITM proteins
Author: Weston, S. M.
ISNI:       0000 0004 7231 2628
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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The InterFeron Inducible TransMembrane proteins (IFITMs) are broad-spectrum antiviral factors. In vitro, these proteins inhibit cellular entry of many enveloped viruses. In vivo, mice lacking expression of all Ifitm genes, or Ifitm3 alone, have been shown to have increased pathogenesis from influenza A, respiratory syncytial, West Nile and chikungunya virus infections. While much is known about the breadth of antiviral action of the IFITM proteins, and more is being learnt about function in vivo, there is currently a poor understanding of aspects of their cell biology and their precise mechanism(s) of antiviral action. The work presented here aims to further understanding of both of these aspects of IFITM biology. Using morphological and biochemical techniques, I first proposed a novel topol- ogy model for the IFITMs, in which the N-terminal domain resides in the cytoplasm, while the C-terminal domain resides in the extracellular/lumenal space. Building on this knowledge, an analysis of the cellular distribution was performed to better understand how the IFITMs interact with the viruses they inhibit. The alphavirus, Semliki Forest virus (SFV) was, for the first time, established as a model system to investigate the antiviral functions of the IFITMs. In these studies I established that IFITM3 blocks viral entry following endocytosis and exposure of virus to low pH and before virus release to the cytoplasm. Finally, the properties of IFITM restriction of SFV were compared to those associated with other viruses that enter cells by similar mechanisms. These experiments showed that related viruses exhibit distinct patterns of IFITM restriction suggesting these different viruses may target distinct membrane sub-domains for fusion. Overall, the work presented here extends our understanding of IFITM membrane topology and cellular distribution, defines IFITM-mediated inhibition of alphavirus infection and raises questions about the mechanisms of inhibition for different IFITM proteins.
Supervisor: Marsh, M. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available