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FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2.
Brevini, Teresa; Maes, Mailis; Webb, Gwilym J; John, Binu V; Fuchs, Claudia D; Buescher, Gustav; Wang, Lu; Griffiths, Chelsea; Brown, Marnie L; Scott, William E; Pereyra-Gerber, Pehuén; Gelson, William T H; Brown, Stephanie; Dillon, Scott; Muraro, Daniele; Sharp, Jo; Neary, Megan; Box, Helen; Tatham, Lee; Stewart, James; Curley, Paul; Pertinez, Henry; Forrest, Sally; Mlcochova, Petra; Varankar, Sagar S; Darvish-Damavandi, Mahnaz; Mulcahy, Victoria L; Kuc, Rhoda E; Williams, Thomas L; Heslop, James A; Rossetti, Davide; Tysoe, Olivia C; Galanakis, Vasileios; Vila-Gonzalez, Marta; Crozier, Thomas W M; Bargehr, Johannes; Sinha, Sanjay; Upponi, Sara S; Fear, Corrina; Swift, Lisa; Saeb-Parsy, Kourosh; Davies, Susan E; Wester, Axel; Hagström, Hannes; Melum, Espen; Clements, Darran; Humphreys, Peter; Herriott, Jo; Kijak, Edyta; Cox, Helen.
  • Brevini T; Wellcome - MRC Cambridge Stem Cell Institute, Cambridge, UK. tb647@cam.ac.uk.
  • Maes M; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Department of Medicine, University of Cambridge, Cambridge, UK.
  • Webb GJ; Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  • John BV; Division of Gastroenterology and Hepatology, University of Miami and Miami VA Health System, Miami, FL, USA.
  • Fuchs CD; Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
  • Buescher G; Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
  • Wang L; Transplant and Regenerative Medicine Laboratory, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
  • Griffiths C; Transplant and Regenerative Medicine Laboratory, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
  • Brown ML; Transplant and Regenerative Medicine Laboratory, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
  • Scott WE; Transplant and Regenerative Medicine Laboratory, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
  • Pereyra-Gerber P; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Department of Medicine, University of Cambridge, Cambridge, UK.
  • Gelson WTH; Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  • Brown S; Department of Medicine, University of Cambridge, Cambridge, UK.
  • Dillon S; Wellcome - MRC Cambridge Stem Cell Institute, Cambridge, UK.
  • Muraro D; Wellcome - MRC Cambridge Stem Cell Institute, Cambridge, UK.
  • Sharp J; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
  • Neary M; Centre of Excellence in Long-acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
  • Box H; Centre of Excellence in Long-acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
  • Tatham L; Centre of Excellence in Long-acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
  • Stewart J; Centre of Excellence in Long-acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
  • Curley P; Department of Infection Biology and Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK.
  • Pertinez H; Centre of Excellence in Long-acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
  • Forrest S; Centre of Excellence in Long-acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
  • Mlcochova P; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Department of Medicine, University of Cambridge, Cambridge, UK.
  • Varankar SS; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Department of Medicine, University of Cambridge, Cambridge, UK.
  • Darvish-Damavandi M; Division of Gastroenterology and Hepatology, University of Miami and Miami VA Health System, Miami, FL, USA.
  • Mulcahy VL; Wellcome - MRC Cambridge Stem Cell Institute, Cambridge, UK.
  • Kuc RE; Wellcome - MRC Cambridge Stem Cell Institute, Cambridge, UK.
  • Williams TL; Nuffield Department of Surgical Sciences, Old Road Campus Research Building, Oxford, UK.
  • Heslop JA; Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK.
  • Rossetti D; Experimental Medicine and Immunotherapeutics, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
  • Tysoe OC; Experimental Medicine and Immunotherapeutics, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
  • Galanakis V; Wellcome - MRC Cambridge Stem Cell Institute, Cambridge, UK.
  • Vila-Gonzalez M; Wellcome - MRC Cambridge Stem Cell Institute, Cambridge, UK.
  • Crozier TWM; Wellcome - MRC Cambridge Stem Cell Institute, Cambridge, UK.
  • Bargehr J; Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research centre, Cambridge, UK.
  • Sinha S; Wellcome - MRC Cambridge Stem Cell Institute, Cambridge, UK.
  • Upponi SS; Wellcome - MRC Cambridge Stem Cell Institute, Cambridge, UK.
  • Fear C; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Department of Medicine, University of Cambridge, Cambridge, UK.
  • Swift L; Wellcome - MRC Cambridge Stem Cell Institute, Cambridge, UK.
  • Saeb-Parsy K; Department of Medicine, University of Cambridge, Cambridge, UK.
  • Davies SE; Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.
  • Wester A; Wellcome - MRC Cambridge Stem Cell Institute, Cambridge, UK.
  • Hagström H; Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.
  • Melum E; Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  • Clements D; Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research centre, Cambridge, UK.
  • Humphreys P; Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research centre, Cambridge, UK.
  • Herriott J; Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research centre, Cambridge, UK.
  • Kijak E; Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  • Cox H; Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Nature ; 2022 Dec 05.
Article in English | MEDLINE | ID: covidwho-2252995
ABSTRACT
Prevention of SARS-CoV-2 infection through the modulation of viral host receptors, such as ACE21, could represent a new chemoprophylactic approach for COVID-19 complementing vaccination2,3. However, the mechanisms controlling ACE2 expression remain elusive. Here, we identify the farnesoid X receptor (FXR) as a direct regulator of ACE2 transcription in multiple COVID19-affected tissues, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone (ZGG) and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We demonstrate 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. Furthermore, we illustrate that UDCA reduces ACE2 expression in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes following SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of liver transplant recipients. In conclusion, we 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, paving the road for future clinical trials.

Full text: Available Collection: International databases Database: MEDLINE Type of study: Cohort study / Observational study / Prognostic study Topics: Vaccines Language: English Year: 2022 Document Type: Article Affiliation country: S41586-022-05594-0

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Full text: Available Collection: International databases Database: MEDLINE Type of study: Cohort study / Observational study / Prognostic study Topics: Vaccines Language: English Year: 2022 Document Type: Article Affiliation country: S41586-022-05594-0