Dataset Information

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 vaccination^2,3. 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.

SUBMITTER: Brevini T

PROVIDER: S-EPMC9977684 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2.

Brevini Teresa T Maes Mailis M Webb Gwilym J GJ John Binu V BV Fuchs Claudia D CD Buescher Gustav G Wang Lu L Griffiths Chelsea C Brown Marnie L ML Scott William E WE Pereyra-Gerber Pehuén P Gelson William T H WTH Brown Stephanie S Dillon Scott S Muraro Daniele D Sharp Jo J Neary Megan M Box Helen H Tatham Lee L Stewart James J Curley Paul P Pertinez Henry H Forrest Sally S Mlcochova Petra P Varankar Sagar S SS Darvish-Damavandi Mahnaz M Mulcahy Victoria L VL Kuc Rhoda E RE Williams Thomas L TL Heslop James A JA Rossetti Davide D Tysoe Olivia C OC Galanakis Vasileios V Vila-Gonzalez Marta M Crozier Thomas W M TWM Bargehr Johannes J Sinha Sanjay S Upponi Sara S SS Fear Corrina C Swift Lisa L Saeb-Parsy Kourosh K Davies Susan E SE Wester Axel A Hagström Hannes H Melum Espen E Clements Darran D Humphreys Peter P Herriott Jo J Kijak Edyta E Cox Helen H Bramwell Chloe C Valentijn Anthony A Illingworth Christopher J R CJR Dahman Bassam B Bastaich Dustin R DR Ferreira Raphaella D RD Marjot Thomas T Barnes Eleanor E Moon Andrew M AM Barritt Alfred S AS Gupta Ravindra K RK Baker Stephen S Davenport Anthony P AP Corbett Gareth G Gorgoulis Vassilis G VG Buczacki Simon J A SJA Lee Joo-Hyeon JH Matheson Nicholas J NJ Trauner Michael M Fisher Andrew J AJ Gibbs Paul P Butler Andrew J AJ Watson Christopher J E CJE Mells George F GF Dougan Gordon G Owen Andrew A Lohse Ansgar W AW Vallier Ludovic L Sampaziotis Fotios F

Nature 20221205 7950

Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)<sup>1</sup>, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination<sup>2,3</sup>. 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. ...[more]

PMID: 36470304

Similar Datasets

Project description:As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have been causing increasingly serious drug resistance problem, development of broadly effective and hard-to-escape anti-SARS-CoV-2 agents is an urgent need. Here, we describe further development and characterization of two SARS-CoV-2 receptor decoy proteins, ACE2-Ig-95 and ACE2-Ig-105/106. We found that both proteins had potent and robust in vitro neutralization activities against diverse SARS-CoV-2 variants, including BQ.1 and XBB.1, that are resistant to most clinically used monoclonal antibodies. In a stringent lethal SARS-CoV-2 infection mouse model, both proteins lowered the lung viral load by up to ~1,000-fold, prevented the emergence of clinical signs in >75% animals, and increased the animal survival rate from 0% (untreated) to >87.5% (treated). These results demonstrate that both proteins are good drug candidates for protecting animals from severe COVID-19. In a head-to-head comparison of these two proteins with five previously described ACE2-Ig constructs, we found that two constructs, each carrying five surface mutations in the ACE2 region, had partial loss of neutralization potency against three SARS-CoV-2 variants. These data suggest that extensively mutating ACE2 residues near the receptor binding domain (RBD)-binding interface should be avoided or performed with extra caution. Furthermore, we found that both ACE2-Ig-95 and ACE2-Ig-105/106 could be produced to the level of grams per liter, demonstrating the developability of them as biologic drug candidates. Stress condition stability testing of them further suggests that more studies are required in the future to improve the stability of these proteins. These studies provide useful insight into critical factors for engineering and preclinical development of ACE2 decoys as broadly effective therapeutics against diverse ACE2-utilizing coronaviruses. IMPORTANCE Engineering soluble ACE2 proteins that function as a receptor decoy to block SARS-CoV-2 infection is a very attractive approach to creating broadly effective and hard-to-escape anti-SARS-CoV-2 agents. This article describes development of two antibody-like soluble ACE2 proteins that broadly block diverse SARS-CoV-2 variants, including Omicron. In a stringent COVID-19 mouse model, both proteins successfully protected >87.5% animals from lethal SARS-CoV-2 infection. In addition, a head-to-head comparison of the two constructs developed in this study with five previously described ACE2 decoy constructs was performed here. Two previously described constructs with relatively more ACE2 surface mutations were found with less robust neutralization activities against diverse SARS-CoV-2 variants. Furthermore, the developability of the two proteins as biologic drug candidates was also assessed here. This study provides two broad anti-SARS-CoV-2 drug candidates and useful insight into critical factors for engineering and preclinical development of ACE2 decoys as broadly effective therapeutics against diverse ACE2-utilizing coronaviruses.

Project description:BackgroundCoronavirus disease 2019 (COVID-19) is an immune-related disorder caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The complete pathogenesis of the virus remains to be determined. Unraveling the molecular mechanisms governing SARS-CoV-2 interactions with host cells is crucial for the formulation of effective prophylactic measures and the advancement of COVID-19 therapeutics.MethodsWe analyzed human lung single-cell RNA sequencing dataset to discern the association of butyrophilin subfamily 3 member A2 (BTN3A2) expression with COVID-19. The BTN3A2 gene edited cell lines and transgenic mice were infected by live SARS-CoV-2 in a biosafety level 3 (BSL-3) laboratory. Immunoprecipitation, flow cytometry, biolayer interferometry and competition ELISA assays were performed in BTN3A2 gene edited cells. We performed quantitative real-time PCR, histological and/or immunohistochemical analyses for tissue samples from mice with or without SARS-CoV-2 infection.FindingsThe BTN3A2 mRNA level was correlated with COVID-19 severity. BTN3A2 expression was predominantly identified in epithelial cells, elevated in pathological epithelial cells from COVID-19 patients and co-occurred with ACE2 expression in the same lung cell subtypes. BTN3A2 targeted the early stage of the viral life cycle by inhibiting SARS-CoV-2 attachment through interactions with the receptor-binding domain (RBD) of the Spike protein and ACE2. BTN3A2 inhibited ACE2-mediated SARS-CoV-2 infection by reducing ACE2 in vitro and in vivo.InterpretationThese results reveal a key role of BTN3A2 in the fight against COVID-19. Identifying potential monoclonal antibodies which mimic BTN3A2 may facilitate disruption of SARS-CoV-2 infection, providing a therapeutic avenue for COVID-19.FundingThis study was supported by the National Natural Science Foundation of China (32070569, U1902215, and 32371017), the CAS "Light of West China" Program, and Yunnan Province (202305AH340006).

Dataset Information

FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2.

Publications

FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets