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dc.contributor.advisorNevels, Michael Martin
dc.contributor.advisorHughes, David John
dc.contributor.authorDeb, Anasua
dc.coverage.spatialxxi, 230 p.en_US
dc.date.accessioned2022-05-18T09:48:53Z
dc.date.available2022-05-18T09:48:53Z
dc.date.issued2022-06-15
dc.identifier.urihttp://hdl.handle.net/10023/25399
dc.description.abstractInterferons (IFN) are an essential component of the vertebrate innate immune system against viruses and other pathogens. Human Cytomegalovirus (HCMV), like other viruses, has developed strategies to evade the host IFN response, enabling lifelong viral persistence in the infected host. In this work, we explore how two HCMV proteins, immediate-early protein 1 (IE1), the first viral protein produced in infected cells, and pUL83, the most abundant protein in the virus particle, counteract the host IFN response in the initial stages of infection by interacting with chromatin. First, we identified the molecular mechanism by which pUL83 interacts with host chromatin using various techniques including fluorescence microscopy and in-vitro histone binding studies. The Linker domain of pUL83 (amino acids 388-479) binds with the core histones for this interaction. The Linker targets the nucleosome acidic patch formed by histones H2A-H2B via residues R₄₅₃ and R₄₅₅. It also has distinct charged residue clusters that mediate binding to all four core histones. Nucleosome targeting by IE1 and pUL83 inhibits host IFN-β and IFN-λ production, enabling HCMV to efficiently spread from the initial infected cell to its neighbouring cells, resulting in the formation of larger and more foci of infection. Our results suggest that inhibition of IFN induction by IE1-nucleosome interaction is unlikely due to changes in nucleosome occupancy, but it may rather be attributable to inhibition of NFkB binding to the IFNB1 promoter. Furthermore, we demonstrate that nucleosome binding by IE1 prevents DNA double strand break repair by non-homologous end joining. Finally, we noticed that IE1-nucleosome interaction limits HCMV reactivation in monocytic cells, allowing the virus to persist in a latent state. Overall, we propose that pUL83 and IE1 promote efficient viral spread by inhibiting IFN gene induction via a novel chromatin-based molecular mechanism involving core histones.en_US
dc.description.sponsorship"This work was supported by a Wellcome Trust Institutional Strategic Support Fund. A part of my tuition fee was covered by a St Leonard’s College Scholarship." -- Acknowledgementsen
dc.language.isoenen_US
dc.publisherUniversity of St Andrews
dc.subjectHuman cytomegalovirusen_US
dc.subjectNucleosome acidic patchen_US
dc.subjectIE1en_US
dc.subjectpUL83en_US
dc.subjectInterferon inhibitionen_US
dc.titleMolecular mechanisms and functional consequences of chromatin binding by the human cytomegalovirus proteins IE1 and pUL83en_US
dc.typeThesisen_US
dc.contributor.sponsorWellcome Trust. Institutional Strategic Support Fund (ISSF)en_US
dc.contributor.sponsorUniversity of St Andrews. St Leonard's College Scholarshipen_US
dc.type.qualificationlevelDoctoralen_US
dc.type.qualificationnamePhD Doctor of Philosophyen_US
dc.publisher.institutionThe University of St Andrewsen_US
dc.rights.embargodate2026-12-14
dc.rights.embargoreasonThesis restricted in accordance with University regulations. Restricted until 14th December 2026en
dc.identifier.doihttps://doi.org/10.17630/sta/174


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