University of Cambridge
Developing novel prophylactic approaches against SARS-CoV-2 infection
Abstract
dc:description.abstractPrevention 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.
Degree
thesis:*- Level dc:type.qualificationlevel
- Doctoral
- Grantor dc:publisher.institution
- University of Cambridge
- Year dc:date.issued
- 2022
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Brevini, Teresa
- Advisor dc:contributor.advisor
-
- Sampaziotis, Fotios
Subjects
dc:subject × 5Rights
dc:rightsIdentifiers
dc:identifier.*- DOI dc:identifier.doi
- https://doi.org/10.17863/CAM.96975
- OAI identifier oai:identifier
- oai:www.repository.cam.ac.uk:1810/350458