1. Introduction
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has lasted for over 3 years and seriously threatens human health. New variants of concern, such as Omicron strains with high transmission ability but lower virulence, have led to the continuous spread of the virus worldwide, including new infections, reinfections, and breakthrough infections of SARS-CoV-2 among different populations. A total of 13 billion vaccine doses had been administered worldwide, and approximately 764 million confirmed cases of COVID-19 had been reported by April 2023.[] Studies have shown that SARS-CoV-2 enters target cells through its spike protein (S protein) binding to the angiotensin-converting enzyme 2 (ACE2) receptor.[] Viral RNA is translated to assemble molecules into a complete viral particle that leaves the cell and strikes another cell. Studies of multiple antiviral agents have been conducted for different targets of the SARS-CoV-2 life cycle. However, the reduced virulence and immune evasion of SARS-CoV-2 variants of concern against neutralizing antibodies raise concerns regarding the effectiveness of the available therapies. Available frontline antiviral drugs, such as molnupiravir[] and nirmatrelvir/ritonavir (Paxlovid),[] suppress viral replication but do not prevent viral infection of target cells. Monoclonal neutralizing antibodies (mAbs) competitively bind to viral receptors but show reduced neutralizing efficacy against new variants.[] Current vaccine-induced antibodies cannot neutralize the virus efficiently because of immune evasion,[] and the concentration of antibodies decreases significantly with time,[] especially in older adults and high-risk groups, such as immunocompromised patients, who are less responsive to vaccines. In particular, the Omicron variant currently prevalent worldwide has greater immune evasion of most mAbs and vaccines than other strains, such as the Alpha, Beta, and Delta variants,[] causing inactivation of neutralizing antibodies and leading to breakthrough infection and reinfection.[] Importantly, no agents are available for the prevention of COVID-19. Therefore, novel agents for the prevention of COVID-19 that can reduce the risk of severe disease are urgently needed.
In contrast to viruses that constantly mutate and escape immune restrictions, ACE2, as the viral host receptor on the cell surface and a pathway used by coronaviruses to invade cells,[] represents a logical therapeutic target because it is the binding target of the S protein of most coronaviruses. Angiotensin-converting enzyme 2 receptors have a high affinity for SARS-CoV-2, and its expression is unaffected by viral mutations.[] A recent study reported that ursodeoxycholic acid (UDCA), which is generally used to treat liver disease,[] can prevent SARS-CoV-2 infection by reducing ACE2 expression. This has subsequently been verified by in vitro and in vivo experiments.[] These findings provide novel and promising data on the potential use of UDCA in the prevention and treatment of COVID-19. Compared with previous COVID-19 prevention strategies, addressing the issue from the host side, such as blocking ACE2 receptors with UDCA to prevent COVID-19, may be a more effective strategy. In this review, we comprehensively summarize the role of ACE2 in SARS-CoV-2 infection and the potential mechanisms by which UDCA may prevent SARS-CoV-2 infection and reinfection, based on recent studies. This review further discusses the unresolved issues and the potential use of UDCA for the treatment of patients with COVID-19.
2. Identification of ACE2 in SARS-CoV-2 infection in host cells
During the viral infection life cycle, viral entry into host target cells through cellular receptors is an important process in infectivity and pathogenicity.[] The receptor for SARS-CoV-2, as for previous coronaviruses, is ACE2[] (Figure 1). ACE2 was discovered in 2000 as a homolog of ACE and is not inhibited by classic ACE inhibitors such as captopril and lisinopril.[] The ACE2 is a type I transmembrane protein with 805 amino acids, which has an extracellular N-terminal structural domain containing a claw-like protease domain (PD) and a short intracellular C-terminal tail named the collectrin-like domain. The N-terminal domain has one active site, the zinc metallopeptidase (HEMGH) domain, which can hydrolyze angiotensin (Ang) I to form Ang 1–9, and Ang II to form Ang 1–7.[] The 40-kb ACE2 gene contains 18 exons, most of which are similar to those of the ACE gene; however, unlike the ACE gene located on human chromosome 17, ACE2 is located on chromosome Xp22. Widespread expression of ACE2 in the lungs, intestine, cardiovascular system, central nervous system, kidney, and adipose tissue highlights how SARS-CoV-2 leads to damage in multiple organs that express ACE2 in their tissue cells.[] Positively correlated with airway epithelial differentiation, lung epithelial cells express higher levels of ACE2 than the upper airways, which leads to SARS-CoV-2 primarily infecting the lungs, rather than the upper airways.[] In the early stages of the COVID-19 global pandemic, studies revealed that SARS-CoV-2 uses ACE2 for entry through its receptor-binding domain (RBD) to initiate viral invasion and the serine protease type II transmembrane serine proteases (TMPRSS2) for S protein priming.[] The RBD of the SARS-CoV-2 S protein binds with the PD of ACE2, forming an RBD-PD complex distinct from the ACE2 catalytic site.[] TMPRSS2 then cleaves the S protein, exposing parts that fuse the viral membrane with that of the host.[] ACE2 is a crucial receptor that plays an essential role in the entry of SARS-CoV-2 into host cells.
Figure 1
SARS-CoV-2 life cycle and currently therapeutic interventions. (1) SARS-CoV-2 binds to the ACE2 receptor on the target cell membrane via the viral spike protein and enters the cell via receptor-mediated endocytosis. TMPRSS2 synergistically activates the spike protein to facilitate viral entry. (2) In the endosome, the viral envelope is removed, and viral RNA is released into the cytoplasm. (3) Intracellularly, genomic RNA is translated into the polypeptides pp1a and pp1ab. (4) Polypeptides are cleaved into corresponding individual nonstructural proteins with diverse biological functions. (5) Individual nonstructural proteins are organized to form replication-transcription complexes (RTCs) for the successive synthesis of viral RNA, including genomic RNA (replication) and subgenomic RNAs (transcription). (6) Subgenomic RNAs encode structural spike, membrane, envelope, and nucleocapsid proteins and several accessory proteins. (7) Genomic RNA coated with nucleocapsid proteins buds into the endoplasmic reticulum–Golgi intermediate compartment (ERGIC) to assemble viral particles. (8) Virions are released from the cell. Current therapeutic drugs (blue boxes) primarily target processes in the viral life cycle. Monoclonal antibodies directly bind to the SARS-CoV-2 spike protein to block viral entry. Antiviral agents mainly interfere with viral replication in target cells. Nirmatrelvir/ritonavir (Paxlovid), an agent targeting 3C-like protease, inhibits polypeptide cleavage. Azvudine and molnupiravir inhibit replication via lethal mutagenesis of the genomes of multiple viruses. More importantly, ursodeoxycholic acid (UDCA) reduces the expression of ACE2 via farnesoid X receptor (FXR) inhibition, thereby blocking the entry of SARS-CoV-2 into the cell. ACE2: Angiotensin-converting enzyme 2; DMV: Double-membrane vesicle; ER: Endoplasmic reticulum; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; TMPRSS2: Type II transmembrane serine proteases.
3. Decreasing ACE2 expression could block SARS-CoV-2 infection and reduce COVID-19 severity
The virus and the host are the key factors affecting SARS-CoV-2 invasion.[] However, drugs targeting the virus are not always effective in preventing infection and reinfection with new variants because of viral mutations and S protein evolution to escape neutralization. Therefore, ACE2, as the viral host receptor on the cell surface, represents a logical therapeutic target because its expression is not affected by mutations in the virus, and it binds directly to the S protein of different coronaviruses, with a high affinity for SARS-CoV-2. Moreover, the highly infectious Omicron variant maintains more robust ACE2 binding than other variants,[] and soluble ACE2 effectively blocks infection.[] Therefore, decreasing the expression of ACE2, which binds to the RBD of the SARS-CoV-2 S protein, is a potential strategy to prevent COVID-19[] (Figure 2).
Figure 2
Interaction between SARS-CoV-2 and the immune system and potential therapeutic targets for each stage of infection. (1) SARS-CoV-2 infection is initiated directly or indirectly through contact with the oral mucosal or by nasal secretions containing infectious respiratory droplets. (2) Viral entry is mediated by the binding of its spike protein to the ACE2 receptor of the target cells in the respiratory tract and lung tissues. Intracellularly, SARS-CoV-2 hijacks the host organelles and nutrients for active and robust replication. (3) SARS-CoV-2 propagation induces a host immune response, not only to defend against viral infection but also lead to tissue injury. The humoral immune response mediated by B cells produces virus-specific antibodies that neutralize infectious particles and stimulate adaptive immunity. T cell–mediated immune responses eliminate infected cells via cytotoxicity or the secretion of antiviral cytokines. (4) The interaction between the virus and the host immune responses influences the progression and outcome of coronavirus disease 2019. The process of SARS-CoV-2 infection includes an incubation phase, clinical progression phase, and a convalescent phase. The boxes show the therapeutic targets during each phase. ACE2: Angiotensin-converting enzyme 2; APC: Antigen-presenting cell; CD: Cluster of differentiation; IFN-γ: Interferon γ; IL-6: Interleukin 6; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; TNF-α: Tumor necrosis factor α; UDCA: Ursodeoxycholic acid.
Brevini et al.[] discovered that blocking the farnesoid X receptor (FXR), a bile acid–sensing protein that is a natural receptor for bile acids,[] reduced the expression of ACE2 on the surface of cells. Using in vitro organoid, in vivo animal, healthy individual, and liver disease cohorts, the authors then demonstrated that UDCA, which is used to treat liver diseases and blocks FXR,[] can reduce ACE2 expression and SARS-CoV-2 infection.[] They found that ACE2 is highly expressed in the bile duct epithelial cells after bile acid intervention. Bile acids do not upregulate ACE2 expression after FXR knockdown, whereas UDCA inhibits FXR stimulated by bile acids to reduce ACE2 expression. Based on these findings, they first infected organoid cells with SARS-CoV-2 in vitro after FXR inhibition and found that the change in viral load was consistent with the trend of ACE reduction and conducted ex vivo experiments on the liver, gallbladder, and a pair of donated lungs. Second, the authors discovered that UDCA reduced ACE2 expression and influenced SARS-CoV-2 infection in hamsters. Third, ACE2 expression in nasal epithelial cells was reduced and returned to normal levels 28 days after discontinuation of the drug among 6 healthy individuals receiving UDCA treatment. Furthermore, in retrospective studies, the authors found that patients with COVID-19 and coexisting diseases, such as chronic liver disease or liver transplantation, who were taking UDCA had a decreased risk of developing severe disease or being hospitalized after SARS-CoV-2 infection and that UDCA administration was correlated with lower serum ACE2 levels.[]
A retrospective cohort study of patients with liver cirrhosis demonstrated that UDCA exposure or use was associated with reduced risk of developing SARS-CoV-2 infection and reduced severity of COVID-19 in patients with cirrhosis.[] Similarly, UDCA use has been associated with increased transplant-free survival in patients with secondary sclerosing cholangitis following COVID-19.[] In addition, UDCA significantly interferes with the binding of S protein to ACE2 in BEAS-2B human bronchial epithelial cells and suppresses abnormal airway epithelial cell migration.[] Docking simulations have indicated that UDCA blocks the binding of RBD and ACE2 in a dose-dependent manner.[] Guggulsterone, another FXR antagonist, has also been shown to be a potential inhibitor of SARS-CoV-2 ADP ribose phosphatase.[] Additionally, evidence suggests that UDCA might interact through multiple mechanisms to reduce the COVID-19 severity. Ursodeoxycholic acid can inhibit proinflammatory cytokines, such as tumor necrosis factor α, interleukin 1β, and interleukin 6,[] and has antioxidant effects.[] Ursodeoxycholic acid increased alveolar fluid clearance through the ALX/cAMP/PI3K pathway in a rat model of acute respiratory distress syndrome.[] Therefore, UDCA is expected to suppress the cytokine storm in patients with COVID-19–associated respiratory failure.[] The reduction in ACE2 expression by FXR inhibitors such as UDCA is considered a novel approach to prevent or treat COVID-19.[]
Notably, there is no evidence that FXR agonists increase the risk of SARS-CoV-2 infection. Instead, FXR agonists, such as obeticholic acid, chenodeoxycholic acid, fexaramine, and ivermectin, may play a critical role in COVID-19.[] An obeticholic acid concentration of 0.98 nmol/L inhibits the binding of SARS-CoV-2 to ACE2 in vitro,[] whereas similar clinical outcomes have been observed in patients with COVID-19 and comorbid autoimmune liver disease.[] Goosodeoxycholic acid limits SARS-CoV-2 proliferation in mice by activating FXR,[] whereas ivermectin acts as an antiviral and anti-inflammatory agent.[] However, it remains unclear whether FXR agonists can prevent SARS-CoV-2 infection.
Several articles have reported preliminary work to prevent COVID-19, based on ACE2 targets.[] Coating mesenchymal stromal cell (MSC) surfaces with anti-ACE2 antibodies have been proposed because of the low homing of MSCs to injured tissue and the competitive binding of ACE2-PD by anti-ACE2–coated MSCs.[] Adhikary et al.[] used biopanning to identify binding partners and discovered and validated a small anti-ACE2 peptide with high specificity and affinity for ACE2 in Vero-E6 cells, which blocked the SARS-CoV-2-RBD/ACE2 interaction. Other studies have found that OM-85 (a standardized lysate of human airway bacteria) and BRD2 suppress SARS-CoV-2 infection ex vivo by downregulating the transcription of ACE2 and TMPRSS2 receptors in host cells and the expression of surface ACE2 protein.[] However, most studies have been supported by limited clinical data or were only preliminary exploratory studies.
4. Critical unresolved issues and suggestions regarding UDCA use for prevention of COVID-19
Despite extensive research, it has not yet been determined whether COVID-19 can be treated or prevented using UDCA. Several critical and unresolved issues need to be addressed, and further research should be conducted to address these concerns. First, no prospective clinical trials involving healthy or infected individuals are available to support the use of UDCA for the prevention of SARS-CoV-2 infection and reinfection. Thus, these findings should be confirmed in cohort studies or randomized controlled trials with large sample sizes. We suggest conducting phase II randomized controlled trials in healthy populations to assess the efficacy of UDCA in reducing the incidence of SARS-CoV-2 infection. Prospective cohort studies of patients with previous SARS-CoV-2 infection in the region of the infection outbreak should be conducted with a 6-month to 1-year follow-up and prophylactic application of UDCA to observe the incidence of reinfection. Second, although the authors found that, through a retrospective analysis of 3 different cohorts, patients taking UDCA for liver conditions had a lower possibility of primary disease deterioration following SARS-CoV-2 infection, retrospective data on whether long-term UDCA administration prevents SARS-CoV-2 infection in liver disease cohorts have not yet been published. The dose and duration of UDCA for the prevention of SARS-CoV-2 infection in healthy individuals require a reference and basis. Bile acids overactivate FXR in patients with cholestasis.[] The plasma concentrations required to reduce ACE2 expression may differ between healthy individuals and those with biliary tract diseases. The effective concentration of UDCA to downregulate ACE2 expression to prevent SARS-CoV-2 infection is unclear, and excessive concentrations may lead to the occurrence of adverse events. Infections in patients on long-term UDCA and not receiving long-term UDCA can be retrospectively analyzed using existing cohorts of patients with chronic liver disease to identify the optimal dose and duration of treatment. Combining the findings from prospective cohort studies, these retrospective results could also contribute to the evidence that the long-term use of UDCA can prevent SARS-CoV-2 infection in different populations. Third, UDCA may be used to prevent SARS-CoV-2 infection; however, its effect on patients with existing SARS-CoV-2 infection is unclear, particularly for the Omicron variant. Thus, prospective studies of SARS-CoV-2 infection and/or reinfection in special and/or priority populations, such as older adults and those with combined primary underlying diseases, are also recommended to observe the efficacy of SARS-CoV-2 reinfection prevention and reduction in the severity of COVID-19, as well as to further determine whether the progression and severity of pneumonia can be reduced by decreasing ACE2 receptors in older adult patients. Furthermore, studies on the immunological mechanisms underlying ACE2 downregulation in COVID-19 prevention using UDCA in different clinical cohorts are lacking. The immune microenvironment and underlying mechanisms in the UDCA cohort of patients with SARS-CoV-2 infection and reinfection should be explored further. In addition, it is necessary to investigate whether patients with primary biliary cholangitis or other cholestatic diseases treated with long-term UDCA have lower susceptibility to reinfection and the related underlying mechanisms, including changes in the FXR/ACE2 pathway.
Briefly, it is critical to review the prevalence and severity of SARS-CoV-2 infection in patients with liver disease receiving UDCA, compare them with their cohabitants, and conduct prospective clinical intervention trials in different populations to assess the efficacy of long-term UDCA use in the prevention of SARS-CoV-2 infection and reinfection. Immunological mechanistic studies should be conducted in parallel with population studies.
5. Prospect of UDCA application for prevention of SARS-COV-2 infection and reinfection
Exploring novel strategies for COVID-19 targeting ACE2 as a therapeutic target is considered reasonable during the early stages of the COVID-19 epidemic.[] Brevini et al.[] identified FXR as a regulator of ACE2 expression and found that UDCA reduced ACE2 expression as an FXR antagonist with significant efficacy to prevent SARS-COV-2 infection. Compared with other agents, such as vaccines and mAbs, UDCA targets ACE2 on the host cell surface rather than on the virus; therefore, it has a high resistance barrier and a broad range of roles against multiple coronaviruses, including viral variants. Ursodeoxycholic acid has been approved by the US Food and Drug Administration for cholestatic liver diseases, such as primary biliary cholangitis and primary sclerosing cholangitis, and is tolerated by most patients without major adverse events.[] Major adverse events include diarrhea and right upper abdominal pain, with a reported incidence of 2% to 9%.[] Adverse reactions may improve significantly without additional management after dose reduction or treatment discontinuation. Additionally, it is easy to administer orally, store, or transport and has the advantages of being affordable and available for large-scale production.
However, the prevention of SARS-CoV-2 reinfection and breakthrough infection remains a major challenge, owing to the variation and immune evasion of the Omicron variant. A cohort study in Qatar showed that 243 of approximately 130,000 SARS-CoV-2 cases were reinfections.[] The 7-day moving average of reinfections in the South African population reached a peak of approximately 2750 during the Omicron variant wave epidemic, whereas the average was only 160 during the Delta variant wave.[] The decrease in neutralizing antibody titers after vaccination also led to breakthrough SARS-CoV-2 infections.[] Moreover, reinfection increases the risk of death, hospitalization, and sequelae in multiple organ systems.[] Prevention of reinfection and/or breakthrough infection is now more important than prevention of the initial SARS-CoV-2 infection. Ursodeoxycholic acid can be used in the long term as a well-tolerated drug to prevent SARS-CoV-2 reinfection and breakthrough infection after COVID-19 recovery and/or vaccination. Large randomized controlled trials are required to assess the clinical efficacy of UDCA. Although the use of UDCA as a substitute for vaccination in patients is not recommended, current findings suggest that it may provide protection against infection in high-risk populations that are not eligible for vaccination.
6. Conclusion
Immune evasion by multiple novel SARS-CoV-2 variants and the limitations of current antibody-based immunotherapies pose new challenges for the prevention of COVID-19 reinfection and breakthrough infection. Inhibition of FXR by UDCA targeting the host cell surface can reduce ACE2 expression, which directly leads to reduced entry of SARS-CoV-2 into target cells in the lungs, liver, and gastrointestinal tract of affected individuals. Therefore, UDCA may serve as a novel drug for the prevention of COVID-19. Considering that its good tolerability, accessibility, and potential benefits have been shown in previous studies, we suggest that multiple clinical trials be conducted as soon as possible to evaluate its efficacy at preventing SARS-CoV-2 infection, reinfection, and breakthrough infection and to explore the possible underlying mechanisms whereby it exerts its effect. This could provide a novel and effective therapeutic strategy for the management of COVID-19, especially in patients with severe comorbidities and older adults.
Funding
The work was supported by grants from the Innovation Groups of the National Natural Science Foundation of China (81721002) and the National Key R&D Program of China (2020YFC0860900).
Author Contributions
Fu-Sheng Wang and Fanping Meng conceived this study. Shida Pan and Yang Zhang drafted the manuscript. Fu-Sheng Wang and Fanping Meng made critical revision of the manuscript. All authors read and approved the final manuscript.
Conflicts of Interest
None.
Editor note: Fu-Sheng Wang is the editor of Infectious Diseases & Immunity. The article was subject to the journal’s standard procedures, with peer review handled independently by this editor and his research group.
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