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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, Vol. 615, No. 7950, 03.2023, p. 134-142.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Brevini, T, Maes, M, Webb, GJ, John, BV, Fuchs, CD, Buescher, G, Wang, L, Griffiths, C, Brown, ML, Scott, WE, Pereyra-Gerber, P, Gelson, WTH, Brown, S, Dillon, S, Muraro, D, Sharp, J, Neary, M, Box, H, Tatham, L, Stewart, J, Curley, P, Pertinez, H, Forrest, S, Mlcochova, P, Varankar, SS, Darvish-Damavandi, M, Mulcahy, VL, Kuc, RE, Williams, TL, Heslop, JA, Rossetti, D, Tysoe, OC, Galanakis, V, Vila-Gonzalez, M, Crozier, TWM, Bargehr, J, Sinha, S, Upponi, SS, Fear, C, Swift, L, Saeb-Parsy, K, Davies, SE, Wester, A, Hagström, H, Melum, E, Clements, D, Humphreys, P, Herriott, J, Kijak, E, Cox, H, Bramwell, C, Valentijn, A, Illingworth, CJR, UK-PBC Consortium, Dahman, B, Bastaich, DR, Ferreira, RD, Marjot, T, Barnes, E, Moon, AM, Barritt, AS, Gupta, RK, Baker, S, Davenport, AP, Corbett, G, Gorgoulis, VG, Buczacki, SJA, Lee, J-H, Matheson, NJ, Trauner, M, Fisher, AJ, Gibbs, P, Butler, AJ, Watson, CJE, Mells, GF, Dougan, G, Owen, A, Lohse, AW, Vallier, L & Sampaziotis, F 2023, 'FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2', NATURE, vol. 615, no. 7950, pp. 134-142. https://doi.org/10.1038/s41586-022-05594-0

APA

Brevini, T., Maes, M., Webb, G. J., John, B. V., Fuchs, C. D., Buescher, G., Wang, L., Griffiths, C., Brown, M. L., Scott, W. E., Pereyra-Gerber, P., Gelson, W. T. H., Brown, S., Dillon, S., Muraro, D., Sharp, J., Neary, M., Box, H., Tatham, L., ... Sampaziotis, F. (2023). FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2. NATURE, 615(7950), 134-142. https://doi.org/10.1038/s41586-022-05594-0

Vancouver

Brevini T, Maes M, Webb GJ, John BV, Fuchs CD, Buescher G et al. FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2. NATURE. 2023 Mar;615(7950):134-142. https://doi.org/10.1038/s41586-022-05594-0

Bibtex

@article{af1c6eaee6a04857961fe1139786d844,
title = "FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2",
abstract = "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.",
author = "Teresa Brevini and Mailis Maes and Webb, {Gwilym J} and John, {Binu V} and Fuchs, {Claudia D} and Gustav Buescher and Lu Wang and Chelsea Griffiths and Brown, {Marnie L} and Scott, {William E} and Pehu{\'e}n Pereyra-Gerber and Gelson, {William T H} and Stephanie Brown and Scott Dillon and Daniele Muraro and Jo Sharp and Megan Neary and Helen Box and Lee Tatham and James Stewart and Paul Curley and Henry Pertinez and Sally Forrest and Petra Mlcochova and Varankar, {Sagar S} and Mahnaz Darvish-Damavandi and Mulcahy, {Victoria L} and Kuc, {Rhoda E} and Williams, {Thomas L} and Heslop, {James A} and Davide Rossetti and Tysoe, {Olivia C} and Vasileios Galanakis and Marta Vila-Gonzalez and Crozier, {Thomas W M} and Johannes Bargehr and Sanjay Sinha and Upponi, {Sara S} and Corrina Fear and Lisa Swift and Kourosh Saeb-Parsy and Davies, {Susan E} and Axel Wester and Hannes Hagstr{\"o}m and Espen Melum and Darran Clements and Peter Humphreys and Jo Herriott and Edyta Kijak and Helen Cox and Chloe Bramwell and Anthony Valentijn and Illingworth, {Christopher J R} and {UK-PBC Consortium} and Bassam Dahman and Bastaich, {Dustin R} and Ferreira, {Raphaella D} and Thomas Marjot and Eleanor Barnes and Moon, {Andrew M} and Barritt, {Alfred S} and Gupta, {Ravindra K} and Stephen Baker and Davenport, {Anthony P} and Gareth Corbett and Gorgoulis, {Vassilis G} and Buczacki, {Simon J A} and Joo-Hyeon Lee and Matheson, {Nicholas J} and Michael Trauner and Fisher, {Andrew J} and Paul Gibbs and Butler, {Andrew J} and Watson, {Christopher J E} and Mells, {George F} and Gordon Dougan and Andrew Owen and Lohse, {Ansgar W} and Ludovic Vallier and Fotios Sampaziotis",
note = "{\textcopyright} 2022. The Author(s).",
year = "2023",
month = mar,
doi = "10.1038/s41586-022-05594-0",
language = "English",
volume = "615",
pages = "134--142",
journal = "NATURE",
issn = "0028-0836",
publisher = "NATURE PUBLISHING GROUP",
number = "7950",

}

RIS

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 -