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dc.contributor.advisorHusain, Matloob
dc.contributor.advisorMercer, Andrew
dc.contributor.authorGalvin, Henry David
dc.date.available2020-02-17T01:17:11Z
dc.date.copyright2020
dc.identifier.citationGalvin, H. D. (2020). The antiviral mechanism and viral antagonism of host histone deacetylase 4 in influenza A virus infection (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/9897en
dc.identifier.urihttp://hdl.handle.net/10523/9897
dc.description.abstractInfluenza virus continues to be an important global pathogen which poses serious health and economic challenges. Influenza virus causes regular seasonal epidemics, intermittent and unpredictable pandemics and deadly zoonotic outbreaks. The currently available antiviral strategies used against influenza are limited in their effectiveness. The rapid evolution of influenza viruses has precluded the development of a universal vaccine and has meant that the annually administered vaccine is only variably effective. Furthermore, the two classes of antiviral drugs used against influenza have only limited effectiveness due to rise in drug resistance. Therefore, there is a pressing need to develop a greater understanding of the virus-host interactions that are critical for influenza virus multiplication and pathogenesis. Such understanding would aid in the development of more effective and long lasting anti-influenza virus strategies. This PhD investigates the role of host histone deacetylase HDAC4, in influenza A virus (IAV) infection, the most significant genus of influenza. Histone deacetylases (HDACs) are a family of enzymes that catalyse the deacetylation of acetylated histone and non-histone proteins. Previously, it has been shown that HDAC1, HDAC2, HDAC6 and HDAC11 all possess anti-influenza virus properties. HDAC1, HDAC2 and HDAC11 are involved in promoting the innate immune response during influenza infection. HDAC6 restricts influenza virus release by deacetylating α-tubulin and decreases viral replication by degrading the viral polymerase and enhancing the RIG-I innate immune response. Currently, no studies have investigated the role of HDAC4 in IAV infection. Given the similarity between different HDAC members, we hypothesised that HDAC4 also plays a role in inhibiting IAV replication. Hence, we investigated the effects of HDAC4 depletion and overexpression on IAV replication using primarily human lung epithelial cells and IAV PR/8/34(H1N1) strain as a model. The outcomes of this project reveal that depletion of HDAC4 enhances the replication of influenza virus by up to 4-fold. Conversely, influenza virus replication was inhibited by up to 49% in cells overexpressing HDAC4, indicating an antiviral role for HDAC4. Mechanistically, HDAC4 was found to be involved in the influenza virus-induced host innate antiviral response. Specifically, we observed decreased phosphorylation of STAT1 in HDAC4 depleted cells, which corresponded to decreased levels of the interferon effector genes (IFITM3, ISG15 and viperin). Conversely, HDAC4 overexpressing cells enhanced STAT1 phosphorylation, resulting in greater expression of the downstream interferon effector genes. We also found that influenza virus actively targets HDAC4 to downregulate its expression both at mRNA and polypeptide levels, likely as a means to inhibit its antiviral function. The HDAC4 mRNA is degraded by the IAV endonuclease PA-X while HDAC4 polypeptide is cleaved by IAV-induced host caspase 3. In summary, the outcomes of this PhD implicate HDAC4 as an anti-influenza host factor that is a component of host innate antiviral response. In addition, it is revealed that influenza virus strongly antagonises HDAC4 to subvert its antiviral activity. Thus, the data presented here contributes to our molecular understanding of host HDACs-influenza virus interplay and strengthening the notion that HDACs are a family of anti-influenza host factors.
dc.format.mimetypeapplication/pdf
dc.language.isoen
dc.publisherUniversity of Otago
dc.rightsAll items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectInfluenza
dc.subjectIAV
dc.subjectHDAC4
dc.subjectIFITM3
dc.subjectPA-X
dc.subjectviperin
dc.subjectISG15
dc.subjectPA
dc.subjectantiviral
dc.subjectpSTAT1
dc.titleThe antiviral mechanism and viral antagonism of host histone deacetylase 4 in influenza A virus infection
dc.typeThesis
dc.date.updated2020-02-05T00:53:37Z
dc.language.rfc3066en
thesis.degree.disciplineMicrobiology and Immunology
thesis.degree.nameDoctor of Philosophy
thesis.degree.grantorUniversity of Otago
thesis.degree.levelDoctoral
otago.openaccessOpen
otago.evidence.presentYes
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