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

Autor: Toshihito Nomura, Takahiro Fukazawa, Hidemasa Bono, Takemasa Sakaguchi, Nobuyuki Hirohashi, Nazmul Tanuza, Kiichi Hirota, Yoshiyuki Matsuo, Keiji Tanimoto
Rok vydání: 2021
Předmět:
Science
media_common.quotation_subject
Carbazoles
Drug Evaluation
Preclinical
Article
Nuclear receptors
Chlorocebus aethiops
Basic Helix-Loop-Helix Transcription Factors
Cytochrome P-450 CYP1A1
Animals
Humans
RNA-Seq
Transcriptomics
Internalization
Receptor
Vero Cells
media_common
Regulation of gene expression
Multidisciplinary
Dose-Response Relationship
Drug
biology
SARS-CoV-2
Chemistry
COVID-19
Hep G2 Cells
Virus Internalization
respiratory system
Aryl hydrocarbon receptor
In vitro
respiratory tract diseases
COVID-19 Drug Treatment
Cell biology
Gene Expression Regulation
Receptors
Aryl Hydrocarbon
Nuclear receptor
Gene Knockdown Techniques
Angiotensin-converting enzyme 2
biology.protein
Medicine
Angiotensin-Converting Enzyme 2
Signal transduction
Omeprazole
hormones
hormone substitutes
and hormone antagonists
Signal Transduction
Zdroj: Scientific Reports
Scientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
ISSN: 2045-2322
Popis: 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.
Databáze: OpenAIRE
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