{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/350458"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/350458","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Developing novel prophylactic approaches against SARS-CoV-2 infection","abstract":"Prevention of SARS-CoV-2 entry into cells through the modulation of viral host receptors, such as ACE2, could represent a new chemoprophylactic and therapeutic approach for COVID- 19 complementing vaccination. However, the mechanisms controlling ACE2 expression remain elusive, partly due to low ACE2 levels in experimental models. To address this challenge, I use biliary epithelial cell (cholangiocyte), one of the cell types with the highest ACE2 levels, to dissect the molecular mechanisms controlling ACE2 expression. I identify the farnesoid X receptor (FXR) as a direct regulator of ACE2 transcription in multiple COVID19- affected tissues, including the gastrointestinal and respiratory systems. I use this knowledge to optimise current experimental models for SARS-CoV-2 infection and I demonstrate that reduction of FXR signalling, with the over-the-counter compound z-guggulsterone (ZGG) and the off-patent drug ursodeoxycholic acid (UDCA), downregulates ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. I also show that UDCA-mediated ACE2 downregulation reduces susceptibility to SARS-CoV- 2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. I then illustrate that UDCA reduces ACE2 expression in the nasal epithelium in humans. Finally, I present a retrospective analysis using an independent patient cohort which identify a correlation between UDCA treatment and positive clinical outcomes following SARS-CoV-2 infection, including hospitalisation, ICU admission and death using retrospective COVID-19 registry data, and confirm these findings in a second independent cohort of liver transplant recipients. In conclusion, with the work described in this dissertation I identify a novel function of FXR in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, thereby paving the road for future clinical trials.","abstract_html":"Prevention of SARS-CoV-2 entry into cells through the modulation of viral host receptors, such as ACE2, could represent a new chemoprophylactic and therapeutic approach for COVID- 19 complementing vaccination. However, the mechanisms controlling ACE2 expression remain elusive, partly due to low ACE2 levels in experimental models. To address this challenge, I use biliary epithelial cell (cholangiocyte), one of the cell types with the highest ACE2 levels, to dissect the molecular mechanisms controlling ACE2 expression. I identify the farnesoid X receptor (FXR) as a direct regulator of ACE2 transcription in multiple COVID19- affected tissues, including the gastrointestinal and respiratory systems. I use this knowledge to optimise current experimental models for SARS-CoV-2 infection and I demonstrate that reduction of FXR signalling, with the over-the-counter compound z-guggulsterone (ZGG) and the off-patent drug ursodeoxycholic acid (UDCA), downregulates ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. I also show that UDCA-mediated ACE2 downregulation reduces susceptibility to SARS-CoV- 2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. I then illustrate that UDCA reduces ACE2 expression in the nasal epithelium in humans. Finally, I present a retrospective analysis using an independent patient cohort which identify a correlation between UDCA treatment and positive clinical outcomes following SARS-CoV-2 infection, including hospitalisation, ICU admission and death using retrospective COVID-19 registry data, and confirm these findings in a second independent cohort of liver transplant recipients. In conclusion, with the work described in this dissertation I identify a novel function of FXR in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, thereby paving the road for future clinical trials.","abstract_has_math":false,"creators":["Brevini, Teresa"],"institution":"University of Cambridge","degree_name":null,"degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Sampaziotis, Fotios"],"committee_chairs":[],"committee_members":[],"year":2022,"date_issued":"2022-09-19","date_published":"2022-09-19","updated_at":"2026-07-22T22:24:24Z","subjects":["COVID-19","Organoids","FXR","Organ perfusion","Translational Medicine"],"languages":["eng"],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/6a69f40d-dff9-4871-bc75-46e534213707/download","http://purl.org/NET/rdflicense/allrightsreserved"],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.96975","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Sampaziotis, Fotios"]},{"key":"dc:creator","label":"Author","values":["Brevini, Teresa"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2022-09-19"]},{"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/1810/350458"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["COVID-19","Organoids","FXR","Organ perfusion","Translational Medicine"]}]},{"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/6a69f40d-dff9-4871-bc75-46e534213707/download","http://purl.org/NET/rdflicense/allrightsreserved"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.17863/CAM.96975"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/d1e8cbc9-0b6c-4e4a-96d7-1755827d90d2/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Prevention of SARS-CoV-2 entry into cells through the modulation of viral host receptors, such as ACE2, could represent a new chemoprophylactic and therapeutic approach for COVID- 19 complementing vaccination. However, the mechanisms controlling ACE2 expression remain elusive, partly due to low ACE2 levels in experimental models. To address this challenge, I use biliary epithelial cell (cholangiocyte), one of the cell types with the highest ACE2 levels, to dissect the molecular mechanisms controlling ACE2 expression. I identify the farnesoid X receptor (FXR) as a direct regulator of ACE2 transcription in multiple COVID19- affected tissues, including the gastrointestinal and respiratory systems. I use this knowledge to optimise current experimental models for SARS-CoV-2 infection and I demonstrate that reduction of FXR signalling, with the over-the-counter compound z-guggulsterone (ZGG) and the off-patent drug ursodeoxycholic acid (UDCA), downregulates ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. I also show that UDCA-mediated ACE2 downregulation reduces susceptibility to SARS-CoV- 2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. I then illustrate that UDCA reduces ACE2 expression in the nasal epithelium in humans. Finally, I present a retrospective analysis using an independent patient cohort which identify a correlation between UDCA treatment and positive clinical outcomes following SARS-CoV-2 infection, including hospitalisation, ICU admission and death using retrospective COVID-19 registry data, and confirm these findings in a second independent cohort of liver transplant recipients. In conclusion, with the work described in this dissertation I identify a novel function of FXR in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, thereby paving the road for future clinical trials."]},{"key":"dc:format.checksum.md5","label":"Dc Format Checksum Md5","values":["7d0cf78ea9662bf9fff40ba74a6341ca","87eda9de84448d1f82354d60eee3eb5f"]},{"key":"dc:title","label":"Title","values":["Developing novel prophylactic approaches against SARS-CoV-2 infection"]}]}],"canonical_facts":{"dc:contributor.advisor":["Sampaziotis, Fotios"],"dc:creator":["Brevini, Teresa"],"dc:date.issued":["2022-09-19"],"dc:description.abstract":["Prevention of SARS-CoV-2 entry into cells through the modulation of viral host receptors, such as ACE2, could represent a new chemoprophylactic and therapeutic approach for COVID- 19 complementing vaccination. However, the mechanisms controlling ACE2 expression remain elusive, partly due to low ACE2 levels in experimental models. To address this challenge, I use biliary epithelial cell (cholangiocyte), one of the cell types with the highest ACE2 levels, to dissect the molecular mechanisms controlling ACE2 expression. I identify the farnesoid X receptor (FXR) as a direct regulator of ACE2 transcription in multiple COVID19- affected tissues, including the gastrointestinal and respiratory systems. I use this knowledge to optimise current experimental models for SARS-CoV-2 infection and I demonstrate that reduction of FXR signalling, with the over-the-counter compound z-guggulsterone (ZGG) and the off-patent drug ursodeoxycholic acid (UDCA), downregulates ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. I also show that UDCA-mediated ACE2 downregulation reduces susceptibility to SARS-CoV- 2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. I then illustrate that UDCA reduces ACE2 expression in the nasal epithelium in humans. Finally, I present a retrospective analysis using an independent patient cohort which identify a correlation between UDCA treatment and positive clinical outcomes following SARS-CoV-2 infection, including hospitalisation, ICU admission and death using retrospective COVID-19 registry data, and confirm these findings in a second independent cohort of liver transplant recipients. In conclusion, with the work described in this dissertation I identify a novel function of FXR in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, thereby paving the road for future clinical trials."],"dc:format.checksum.md5":["7d0cf78ea9662bf9fff40ba74a6341ca","87eda9de84448d1f82354d60eee3eb5f"],"dc:identifier.doi":["https://doi.org/10.17863/CAM.96975"],"dc:identifier.uri":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/d1e8cbc9-0b6c-4e4a-96d7-1755827d90d2/download"],"dc:language":["eng"],"dc:publisher.institution":["University of Cambridge"],"dc:relation.isreferencedby.uri":["https://www.repository.cam.ac.uk/handle/1810/350458"],"dc:rights":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/6a69f40d-dff9-4871-bc75-46e534213707/download","http://purl.org/NET/rdflicense/allrightsreserved"],"dc:subject":["COVID-19","Organoids","FXR","Organ perfusion","Translational Medicine"],"dc:title":["Developing novel prophylactic approaches against SARS-CoV-2 infection"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["Doctoral"]},"updated_at":"2026-07-22T22:24:24Z"}