Inhibiting SARS-CoV-2 infection in vitro by suppressing its receptor, angiotensin-converting enzyme 2, via aryl-hydrocarbon receptor signal

Abstract

Since understanding molecular mechanisms of SARS-CoV-2 infection is extremely important for developing effective therapies against COVID-19, we focused on the internalization mechanism of SARS-CoV-2 via ACE2. Although cigarette smoke is generally believed to be harmful to the pathogenesis of COVID-19, cigarette smoke extract (CSE) treatments were surprisingly found to suppress the expression of ACE2 in HepG2 cells. We thus tried to clarify the mechanism of CSE effects on expression of ACE2 in mammalian cells. Because RNA-seq analysis suggested that suppressive effects on ACE2 might be inversely correlated with induction of the genes regulated by aryl hydrocarbon receptor (AHR), the AHR agonists 6-formylindolo(3,2-b)carbazole (FICZ) and omeprazole (OMP) were tested to assess whether those treatments affected ACE2 expression. Both FICZ and OMP clearly suppressed ACE2 expression in a dose-dependent manner along with inducing CYP1A1. Knock-down experiments indicated a reduction of ACE2 by FICZ treatment in an AHR-dependent manner. Finally, treatments of AHR agonists inhibited SARS-CoV-2 infection into Vero E6 cells as determined with immunoblotting analyses detecting SARS-CoV-2 specific nucleocapsid protein. We here demonstrate that treatment with AHR agonists, including FICZ, and OMP, decreases expression of ACE2 via AHR activation, resulting in suppression of SARS-CoV-2 infection in mammalian cells.

Experimental Models of COVID-19

“…Vero E6 cell lines have also been used in multiple studies of SARS-CoV-2 repurposed antivirals ( Canal et al., 2021 , Leneva et al., 2021 ), protease inhibitors ( Cui and Jia, 2021 ; Han et al., 2021 ) as well as inhibiting peptides ( Kelesidis et al., 2021 ). This cell line model was used in research investigating the indirect inhibition of the ACE-2 receptor as a possible SARS-CoV-2 therapeutic ( Tanimoto et al., 2021 ) along with human polyclonal IgG ( Gilliland et al., 2021 ). Treating SARS-CoV-2 infection with repurposed drugs has been an area of intense research due to the speed at which these therapeutics can be approved and implemented into the clinical setting.…”

Hypothesis: Emerging Roles for Aryl Hydrocarbon Receptor in Orchestrating CoV-2-Related Inflammation

“…However, it must be considered that these data are preliminary and that the anti-androgenic effect of FICZ, which also reverberates on DHT and Prostate-Specific Antigen (PSA) levels, could be a serious side-effect of a hypothetical FICZ-based anti-COVID-19 therapy. An interesting discrepancy concerning AhR involvement in the management of SARS-CoV-2 infection comes from Tanimoto’s study [ 31 ] that recently highlighted an inverse correlation between ACE-2 expression and AHR activation in non-respiratory mammalian cell lines using its agonists FICZ, omeprazole (OMP) and Cigarette Smoke Extract (CSE). According to Tanimoto’s data, the more the AHR pathway is activated, the less ACE-2 is expressed, and consequently, the viral load decreases.…”

The Impact of Sociodemographic, Nutritional, and Health Factors on the Incidence and Complications of COVID-19 in Egypt: A Cross-Sectional Study

“…Another explanation was provided by Tanimoto et al, (2021), who reported that cigarette smoke extract (CSE) treatments were, surprisingly, found to suppress the expression of ACE2 in HepG2 cells [ 22 ]. Interestingly, the effect of smoking on the Antibody titer after vaccination is inverted.…”