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Title: Determining the role of histone modification during Vaccinia virus infection
Author: Garcia Calavia, Noelia
ISNI:       0000 0004 7660 5938
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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Vaccinia is a Poxvirus widely known as the vaccine used to eradicate Smallpox in 1980. Today, it is extensively used in research as an easy to work with biological tool. Unlike most viruses, it replicates in the cell cytoplasm and for decades it had been postulated that the nucleus is not necessary for viral infection. As a consequence, interactions between Vaccinia and the cell nucleus have been overlooked. Recently, some studies have shown that the virus recruits host cell nuclear proteins to replication factories in order to facilitate transcription. However, little is known about the extent and nature of poxvirus-nucleus interactions. We know that pathogens modulate cell chromatin, by controlling histone marks, in order to dampen the cell's immune response. This project sheds light on the mechanisms used by Vaccinia to modulate host cell chromatin. We have special interest in how the virus may be preventing the expression of immune response genes. Using Immunofluorecence and Cell fractionation I have seen one phosphatase (H1) enter the cell nucleus during infection. A survey of histone modifications during the course of infection showed a drastic decrease in the phosphorylation of Histone 3 at Threonine 3, Serine 10, and Serine 28. As H3 S10 has been linked to cytokine gene repression I followed up this mark. I show, using in vitro dephosphorylation assays and cell transfections, that the Vaccinia phosphatase H1 is partially responsible for H3 S10 dephosphorylation. I further link this phenotype to dampening of the cellular immune response through reduction of cytokine gene expression. Finally, though modulation of H3 S10 phosphorylation I demonstrate that this modification is vital for productive Vaccinia infection.
Supervisor: Mercer, J. ; Henriques, R. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available