{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/368745"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/368745","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Gene expression during the host-bacteria interaction","abstract":"The gene expression profile of both host and pathogen can be altered dramatically upon their interaction. This response is shaped by the co-evolutionary arms race where the host seeks to detect and counter the invading pathogen, whilst the pathogen aims to evade this response and modify the host to better suit its survival and replication. Changes in gene expression during infection are thus the net result of these competing goals, the balance of which can ultimately determine the infection outcome. While the transcriptional response to bacterial infection is well studied, the analysis of gene expression is incomplete without also looking at translation. Translation regulation allows for a more rapid and dynamic response than transcriptional regulation and it is well characterized that translation is highly modulated under stress, including in infection. Where there are many studies on the translational response to viral infection, the translational response to bacterial pathogens is understudied. This thesis centres on the changes in host macrophage transcription and translation upon infection with intracellular pathogenic bacteria, with the aim to uncouple the contribution of various bacterial features or intracellular life cycle stages from the more general response to the bacteria. For this, I utilise the Gram-negative bacteria Salmonella Typhimurium and the Gram-positive bacteria Listeria monocytogenes. As such, I can identify both responses in common and unique to the two very different intra-cellular bacterial pathogens. In Salmonella infection, detection of bacterial LPS by TLR4 is critical to mount a rapid immune response. TLR4 activation has been well studied in isolation as a driver in increasing transcription and translation of immune response genes. However, stimulation of TLR4 by purified LPS does not recapitulate how it will be activated in an infection and excludes potential competing or synergising pathways that are activated by invading bacteria. As such, using host TLR4 mutants and bacterial invasion mutants, I am able to uncouple the TLR4-specific changes in host transcription and translation in Gram-negative bacterial infection. Unlike Salmonella, after invading a host cell Listeria do not remain in a vesicle. Rather, they lyse the endosome and enter the host cytoplasm. As such, the machinery that detects the infecting Listeria differs depending on the stage in the Listeria intracellular lifecycle. Therefore, by utilising mutants that stall Listeria at various lifecycle stages, I can tie specific transcriptional and translational responses to a specific lifecycle stage. From this not only do I gain insight into the temporal dynamics of gene expression in response to Listeria infection, but I can also link it to the specific modes of Listeria detection.","abstract_html":"The gene expression profile of both host and pathogen can be altered dramatically upon their interaction. This response is shaped by the co-evolutionary arms race where the host seeks to detect and counter the invading pathogen, whilst the pathogen aims to evade this response and modify the host to better suit its survival and replication. Changes in gene expression during infection are thus the net result of these competing goals, the balance of which can ultimately determine the infection outcome. While the transcriptional response to bacterial infection is well studied, the analysis of gene expression is incomplete without also looking at translation. Translation regulation allows for a more rapid and dynamic response than transcriptional regulation and it is well characterized that translation is highly modulated under stress, including in infection. Where there are many studies on the translational response to viral infection, the translational response to bacterial pathogens is understudied. This thesis centres on the changes in host macrophage transcription and translation upon infection with intracellular pathogenic bacteria, with the aim to uncouple the contribution of various bacterial features or intracellular life cycle stages from the more general response to the bacteria. For this, I utilise the Gram-negative bacteria Salmonella Typhimurium and the Gram-positive bacteria Listeria monocytogenes. As such, I can identify both responses in common and unique to the two very different intra-cellular bacterial pathogens. In Salmonella infection, detection of bacterial LPS by TLR4 is critical to mount a rapid immune response. TLR4 activation has been well studied in isolation as a driver in increasing transcription and translation of immune response genes. However, stimulation of TLR4 by purified LPS does not recapitulate how it will be activated in an infection and excludes potential competing or synergising pathways that are activated by invading bacteria. As such, using host TLR4 mutants and bacterial invasion mutants, I am able to uncouple the TLR4-specific changes in host transcription and translation in Gram-negative bacterial infection. Unlike Salmonella, after invading a host cell Listeria do not remain in a vesicle. Rather, they lyse the endosome and enter the host cytoplasm. As such, the machinery that detects the infecting Listeria differs depending on the stage in the Listeria intracellular lifecycle. Therefore, by utilising mutants that stall Listeria at various lifecycle stages, I can tie specific transcriptional and translational responses to a specific lifecycle stage. From this not only do I gain insight into the temporal dynamics of gene expression in response to Listeria infection, but I can also link it to the specific modes of Listeria detection.","abstract_has_math":false,"creators":["Wood, George"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Chung, Betty"],"committee_chairs":[],"committee_members":[],"year":2023,"date_issued":"2023-09-01","date_published":"2023-09-01","updated_at":"2026-07-22T22:24:27Z","subjects":["host-pathogen interaction","gene expression","translation","transcription","Salmonella","Listeria","bacterial infection","TLR4","toll-like receptor","ribosome profiling"],"languages":["eng"],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/0aa5a078-5496-416d-abb9-492267f28b55/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.108835","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Chung, Betty"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["Supported by the Department of Pathology PhD studentship"]},{"key":"dc:creator","label":"Author","values":["Wood, George"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2023-09-01"]},{"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/1810/368745"]},{"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":["host-pathogen interaction","gene expression","translation","transcription","Salmonella","Listeria","bacterial infection","TLR4","toll-like receptor","ribosome profiling"]}]},{"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/0aa5a078-5496-416d-abb9-492267f28b55/download","https://www.rioxx.net/licenses/all-rights-reserved/"]},{"key":"dc:rights.embargodate","label":"Dc Rights Embargodate","values":["2028-05-23"]},{"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.108835"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/fa8fa8e4-da04-43bf-9969-d7e4394a143f/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["The gene expression profile of both host and pathogen can be altered dramatically upon their interaction. 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