{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/376979"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/376979","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Natural Killer Cell Responses to Human Cytomegalovirus","abstract":"Human cytomegalovirus (HCMV), a member of the beta-herpesvirus family, establishes latent infection in the face of robust humoral and cell-mediated immune responses. In spite of significant efforts, the mechanisms implicated in protective immunity during HCMV infection are still not fully understood. To evade the potent and diverse natural killer (NK) cell mediated- effector functions, HCMV encodes an array of immunoevasins and perturbs the NK cell receptor repertoire with considerable inter-and intra-individual heterogeneity. While certain NK subsets expand in response to HCMV infection, it is unclear whether these subsets have functional implications. Consequently, an in-depth phenotypic and functional dissection of NK cells is required to gain a better insight of how NK cells mediate their effector responses upon recognising HCMV. The work presented in this thesis utilises a viral dissemination assay (VDA) to study the relationship between NK cell function and phenotype in controlling in vitro HCMV infection using healthy HCMV-seropositive and HCMV-seronegative donors. VDA revealed that the antiviral activity of NK cells was not influenced by HCMV serostatus of donors. Distinct phenotypic signatures on NK cells exhibiting enhanced functional control were further identified. The role of NK cell memory recall responses in influencing effector function of NK cells was also investigated. The antiviral activity of expanded and rested NK cells reverted to baseline in both seropositive donors but was enhanced in the expanded and rested NK cells of seronegative donor. Distinct HCMV-induced NK cell immunotypes emerged following co-culture of NK cells with HCMV-infected fibroblasts and were characterised via multi-dimensional clustering analysis. Inter-donor variations in NK cell-mediated antibody dependent viral control (ADVC) in HCMV-seropositive donors were revealed and a positive correlation between anti-UL141 antibodies and a robust ADVC activity was confirmed. Lastly, crosstalk of NK cells, monocytes, and HCMV-specific antibodies potentiated in vitro control of HCMV dissemination with a marked increase in IFN-γ, TNF-α, and IL-1β cytokines. IL-1β emerged as an intriguing cytokine displaying a differential in its ability to restrict late gene expression. While key cytokines and chemokines were detected via RNA sequencing following IL-1β-treatment of HCMV-infected fibroblasts, no distinct antiviral pathways were implicated in IL-1β-mediated viral control. Collectively, these findings contribute to our understanding of the complex interplay between NK cells and HCMV that will be important for the development of NK cell-based therapeutic approaches.","abstract_html":"Human cytomegalovirus (HCMV), a member of the beta-herpesvirus family, establishes latent infection in the face of robust humoral and cell-mediated immune responses. In spite of significant efforts, the mechanisms implicated in protective immunity during HCMV infection are still not fully understood. To evade the potent and diverse natural killer (NK) cell mediated- effector functions, HCMV encodes an array of immunoevasins and perturbs the NK cell receptor repertoire with considerable inter-and intra-individual heterogeneity. While certain NK subsets expand in response to HCMV infection, it is unclear whether these subsets have functional implications. Consequently, an in-depth phenotypic and functional dissection of NK cells is required to gain a better insight of how NK cells mediate their effector responses upon recognising HCMV. The work presented in this thesis utilises a viral dissemination assay (VDA) to study the relationship between NK cell function and phenotype in controlling in vitro HCMV infection using healthy HCMV-seropositive and HCMV-seronegative donors. VDA revealed that the antiviral activity of NK cells was not influenced by HCMV serostatus of donors. Distinct phenotypic signatures on NK cells exhibiting enhanced functional control were further identified. The role of NK cell memory recall responses in influencing effector function of NK cells was also investigated. The antiviral activity of expanded and rested NK cells reverted to baseline in both seropositive donors but was enhanced in the expanded and rested NK cells of seronegative donor. Distinct HCMV-induced NK cell immunotypes emerged following co-culture of NK cells with HCMV-infected fibroblasts and were characterised via multi-dimensional clustering analysis. Inter-donor variations in NK cell-mediated antibody dependent viral control (ADVC) in HCMV-seropositive donors were revealed and a positive correlation between anti-UL141 antibodies and a robust ADVC activity was confirmed. Lastly, crosstalk of NK cells, monocytes, and HCMV-specific antibodies potentiated in vitro control of HCMV dissemination with a marked increase in IFN-γ, TNF-α, and IL-1β cytokines. IL-1β emerged as an intriguing cytokine displaying a differential in its ability to restrict late gene expression. While key cytokines and chemokines were detected via RNA sequencing following IL-1β-treatment of HCMV-infected fibroblasts, no distinct antiviral pathways were implicated in IL-1β-mediated viral control. Collectively, these findings contribute to our understanding of the complex interplay between NK cells and HCMV that will be important for the development of NK cell-based therapeutic approaches.","abstract_has_math":false,"creators":["Noor, Mahlaqua"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Wills, Mark"],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-09-28","date_published":"2024-09-28","updated_at":"2026-07-22T22:24:23Z","subjects":["Natural Killer cells","Cytomegalovirus"],"languages":["eng"],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/aeac9232-c6a6-46fe-a37b-ef2ca3cd2e41/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.113998","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Wills, Mark"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["Gates Cambridge Scholarship"]},{"key":"dc:creator","label":"Author","values":["Noor, Mahlaqua"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2024-09-28"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/376979"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Natural Killer cells","Cytomegalovirus"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/aeac9232-c6a6-46fe-a37b-ef2ca3cd2e41/download","https://www.rioxx.net/licenses/all-rights-reserved/"]},{"key":"dc:rights.embargodate","label":"Dc Rights Embargodate","values":["2025-12-04"]},{"key":"dc:rights.embargotype","label":"Dc Rights Embargotype","values":["embargo"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.17863/CAM.113998"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/24f12f52-f871-4cfb-bacd-ea71a19e1ff0/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Human cytomegalovirus (HCMV), a member of the beta-herpesvirus family, establishes latent infection in the face of robust humoral and cell-mediated immune responses. 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VDA revealed that the antiviral activity of NK cells was not influenced by HCMV serostatus of donors. Distinct phenotypic signatures on NK cells exhibiting enhanced functional control were further identified. The role of NK cell memory recall responses in influencing effector function of NK cells was also investigated. The antiviral activity of expanded and rested NK cells reverted to baseline in both seropositive donors but was enhanced in the expanded and rested NK cells of seronegative donor. Distinct HCMV-induced NK cell immunotypes emerged following co-culture of NK cells with HCMV-infected fibroblasts and were characterised via multi-dimensional clustering analysis. Inter-donor variations in NK cell-mediated antibody dependent viral control (ADVC) in HCMV-seropositive donors were revealed and a positive correlation between anti-UL141 antibodies and a robust ADVC activity was confirmed. Lastly, crosstalk of NK cells, monocytes, and HCMV-specific antibodies potentiated in vitro control of HCMV dissemination with a marked increase in IFN-γ, TNF-α, and IL-1β cytokines. IL-1β emerged as an intriguing cytokine displaying a differential in its ability to restrict late gene expression. While key cytokines and chemokines were detected via RNA sequencing following IL-1β-treatment of HCMV-infected fibroblasts, no distinct antiviral pathways were implicated in IL-1β-mediated viral control. 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To evade the potent and diverse natural killer (NK) cell mediated- effector functions, HCMV encodes an array of immunoevasins and perturbs the NK cell receptor repertoire with considerable inter-and intra-individual heterogeneity. While certain NK subsets expand in response to HCMV infection, it is unclear whether these subsets have functional implications. Consequently, an in-depth phenotypic and functional dissection of NK cells is required to gain a better insight of how NK cells mediate their effector responses upon recognising HCMV. The work presented in this thesis utilises a viral dissemination assay (VDA) to study the relationship between NK cell function and phenotype in controlling in vitro HCMV infection using healthy HCMV-seropositive and HCMV-seronegative donors. VDA revealed that the antiviral activity of NK cells was not influenced by HCMV serostatus of donors. Distinct phenotypic signatures on NK cells exhibiting enhanced functional control were further identified. The role of NK cell memory recall responses in influencing effector function of NK cells was also investigated. The antiviral activity of expanded and rested NK cells reverted to baseline in both seropositive donors but was enhanced in the expanded and rested NK cells of seronegative donor. Distinct HCMV-induced NK cell immunotypes emerged following co-culture of NK cells with HCMV-infected fibroblasts and were characterised via multi-dimensional clustering analysis. Inter-donor variations in NK cell-mediated antibody dependent viral control (ADVC) in HCMV-seropositive donors were revealed and a positive correlation between anti-UL141 antibodies and a robust ADVC activity was confirmed. Lastly, crosstalk of NK cells, monocytes, and HCMV-specific antibodies potentiated in vitro control of HCMV dissemination with a marked increase in IFN-γ, TNF-α, and IL-1β cytokines. IL-1β emerged as an intriguing cytokine displaying a differential in its ability to restrict late gene expression. While key cytokines and chemokines were detected via RNA sequencing following IL-1β-treatment of HCMV-infected fibroblasts, no distinct antiviral pathways were implicated in IL-1β-mediated viral control. 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