Virus and interferon : a fight for supremacy : comparison of the mechanisms of influenza A viruses and parainfluenza virus 5 in combatting a pre-existing IFN-induced antiviral state
View/ Open
Date
06/06/2011Author
Supervisor
Funder
Metadata
Show full item recordAltmetrics Handle Statistics
Abstract
The Interferon (IFN) family of cytokines are produced in direct response to virus infection and they constitute the first line of defence against virus infection by inducing hundreds of interferon stimulated genes (ISGs) which act in concert to establish the so-called “antiviral state”. Influenza A viruses and parainfluenza virus type 5 (PIV5) are both small negative strand RNA viruses that must circumvent their hosts’ interferon (IFN) response for replication. However, the ways in which these viruses interact with the IFN system are very different. Although PIV5 replication is initially severely impaired in cells in a pre-existing IFN-induced antiviral state, it manages to overcome the antiviral state by targeting an essential component of type I IFN signalling, STAT1, for degradation. Thus the cells cannot maintain the antiviral state indefinitely without continuous signalling. Consequently, the virus resumes its normal replication pattern after 24-48 hours post-infection. In clear contrast, influenza virus fails to establish its replication in the majority of infected cells (90-95%) with a pre-existing IFN-induced antiviral state, although a few cells are still able to produce viral antigens.
To further investigate how influenza virus interacts with cells in a pre-existing IFN-induced antiviral state, I have used in situ hybridization to follow the fate of input and progeny genomes in cells that have, or have not, been treated with IFN prior to infection. Here I show for the first time that IFN pre-treatment blocks the nuclear import of influenza A virus genome, which prevents the establishment of virus replication, but this can be overcome by increasing multiplicities of infection. Of those IFN-induced antiviral molecules, human MxA is an essential component of the IFN-induced antiviral state in blocking influenza virus genome import, as this block can be abolished by lentivirus-mediated knockdown of MxA. I also show that in cells constitutively expressing MxA the viral genome still manages to be transported into the nucleus, indicating that MxA might require an unidentified IFN-induced factor to block nuclear import of the influenza virus genome.
These results reveal that IFN exerts its action at an early stage of virus infection by inducing MxA to interfere with the transport of viral genome into the nucleus, which is the factory for viral RNA production.
Type
Thesis, PhD Doctor of Philosophy
Collections
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.
Related items
Showing items related by title, author, creator and subject.
-
Molecular studies of the Tacaribe virus nucleoprotein (NP): identification and characterisation of virus-host interactions as novel anti-arenavirus drug targets
Meyer, Bjoern (University of St Andrews, 2014) - ThesisArenaviruses cause an estimated 300,000 – 500,000 infections annually. Currently there is no arenavirus-specific antiviral drug available to treat these infections. This study sought to use the non-pathogenic New World ... -
Structural studies on a hepatitis C virus-related immunological complex and on Ebola virus polymerase cofactor VP35
Fadda, Valeria (University of St Andrews, 2015-11-30) - ThesisHepatitis C virus (HCV) is one of the leading causes of hepatocellular carcinoma worldwide. HCV-neutralizing antibody AP33 recognizes a linear, highly conserved epitope on the viral entry protein E2, disrupting the interaction ... -
Viruses and the interferon (IFN) response : methods to improve production and to rapidly select IFN-sensitive viruses for vaccine development
Stewart, Claire Emma (University of St Andrews, 2017) - ThesisManipulation of a virus’s capacity to circumvent the interferon (IFN) response aids both fundamental studies as well as many practical applications including the design of live-attenuated vaccines. However, these ...