FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2
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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; Bramwell, Chloe; Valentijn, Anthony; Illingworth, Christopher J R; UK-PBC Consortium; Dahman, Bassam; Bastaich, Dustin R; Ferreira, Raphaella D; Marjot, Thomas; Barnes, Eleanor; Moon, Andrew M; Barritt, Alfred S; Gupta, Ravindra K; Baker, Stephen; Davenport, Anthony P; Corbett, Gareth; Gorgoulis, Vassilis G; Buczacki, Simon J A; Lee, Joo-Hyeon; Matheson, Nicholas J; Trauner, Michael; Fisher, Andrew J; Gibbs, Paul; Butler, Andrew J; Watson, Christopher J E; Mells, George F; Dougan, Gordon; Owen, Andrew; Lohse, Ansgar W; Vallier, Ludovic; Sampaziotis, Fotios.
in: NATURE, Jahrgang 615, Nr. 7950, 03.2023, S. 134-142.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2
AU - Brevini, Teresa
AU - Maes, Mailis
AU - Webb, Gwilym J
AU - John, Binu V
AU - Fuchs, Claudia D
AU - Buescher, Gustav
AU - Wang, Lu
AU - Griffiths, Chelsea
AU - Brown, Marnie L
AU - Scott, William E
AU - Pereyra-Gerber, Pehuén
AU - Gelson, William T H
AU - Brown, Stephanie
AU - Dillon, Scott
AU - Muraro, Daniele
AU - Sharp, Jo
AU - Neary, Megan
AU - Box, Helen
AU - Tatham, Lee
AU - Stewart, James
AU - Curley, Paul
AU - Pertinez, Henry
AU - Forrest, Sally
AU - Mlcochova, Petra
AU - Varankar, Sagar S
AU - Darvish-Damavandi, Mahnaz
AU - Mulcahy, Victoria L
AU - Kuc, Rhoda E
AU - Williams, Thomas L
AU - Heslop, James A
AU - Rossetti, Davide
AU - Tysoe, Olivia C
AU - Galanakis, Vasileios
AU - Vila-Gonzalez, Marta
AU - Crozier, Thomas W M
AU - Bargehr, Johannes
AU - Sinha, Sanjay
AU - Upponi, Sara S
AU - Fear, Corrina
AU - Swift, Lisa
AU - Saeb-Parsy, Kourosh
AU - Davies, Susan E
AU - Wester, Axel
AU - Hagström, Hannes
AU - Melum, Espen
AU - Clements, Darran
AU - Humphreys, Peter
AU - Herriott, Jo
AU - Kijak, Edyta
AU - Cox, Helen
AU - Bramwell, Chloe
AU - Valentijn, Anthony
AU - Illingworth, Christopher J R
AU - UK-PBC Consortium
AU - Dahman, Bassam
AU - Bastaich, Dustin R
AU - Ferreira, Raphaella D
AU - Marjot, Thomas
AU - Barnes, Eleanor
AU - Moon, Andrew M
AU - Barritt, Alfred S
AU - Gupta, Ravindra K
AU - Baker, Stephen
AU - Davenport, Anthony P
AU - Corbett, Gareth
AU - Gorgoulis, Vassilis G
AU - Buczacki, Simon J A
AU - Lee, Joo-Hyeon
AU - Matheson, Nicholas J
AU - Trauner, Michael
AU - Fisher, Andrew J
AU - Gibbs, Paul
AU - Butler, Andrew J
AU - Watson, Christopher J E
AU - Mells, George F
AU - Dougan, Gordon
AU - Owen, Andrew
AU - Lohse, Ansgar W
AU - Vallier, Ludovic
AU - Sampaziotis, Fotios
N1 - © 2022. The Author(s).
PY - 2023/3
Y1 - 2023/3
N2 - Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone 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 show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.
AB - Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone 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 show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.
U2 - 10.1038/s41586-022-05594-0
DO - 10.1038/s41586-022-05594-0
M3 - SCORING: Journal article
C2 - 36470304
VL - 615
SP - 134
EP - 142
JO - NATURE
JF - NATURE
SN - 0028-0836
IS - 7950
ER -