Cigarette Smoke Stimulates SARS-CoV-2 Internalization

The angiotensin-converting enzyme 2 (ACE2) receptor and the transmembrane serine protease 2 (TMPRSS2) are used by SARS-CoV-2 for entry and priming respectively into the host cells and are expressed in the human gingival epithelial cells (GEC). Upon exposing the GEC to 1 µg/mL and 10 µg/mL or 100 µg/mL of cigarette smoke condensate (CSC) in-vitro, there was a 2-fold and 2.5-fold increase respectively in the expression of ACE2 receptors. But, CSC had a less prominent effect on the expression of TMPRSS2.


Aryl Hydrocarbon Receptor (Ahr), a ubiquitously-expressed transcription factor is activated by cigarette smoke and translocates into the nucleus upon activation. Ahr in GECs was activated and nuclear translocation was induced when treated with 1 or 10 µg/mL of CSC. Moreover, Ahr activation by 1 µg/mL of 2,3,7,8-tetrachlo rodibenzo-p-dioxin (TCDD) or CSC for 24 hrs upregulated the expression of ACE2. However, TMPRSS2 expression levels did not significantly increase when treated with 10 µg/mL TCDD or CSC.


This proves that Ahr activation is involved in the increase of ACE2, but not TMPRSS2. To analyze the effect of CSC on the internalization of the SARS-CoV-2 virus, GECs with or without TCDD (10 nM) or CSC (1 or 10 µg/mL) was infected with SARS-CoV-2 GFP-tagged pseudovirus and analyzed using immunofluorescence microscopy. It was observed that GECs treated with CSC at 10 µg/mL showed a significant increase in SARS-CoV-2 pseudovirus infection when compared to untreated cells. Similarly, CSC exposed GECs when treated with siRNA against Ahr showed lower levels of SARS-CoV-2 pseudovirus internalization.


The angiotensin-converting enzyme 2 (ACE2) receptor and the transmembrane serine protease 2 (TMPRSS2) are used by SARS-CoV-2 for entry and priming respectively into the host cells and are expressed in the human gingival epithelial cells (GEC). Upon exposing the GEC to 1 µg/mL and 10 µg/mL or 100 µg/mL of cigarette smoke condensate (CSC) in-vitro, there was a 2-fold and 2.5-fold increase respectively in the expression of ACE2 receptors. But, CSC had a less prominent effect on the expression of TMPRSS2. Aryl Hydrocarbon Receptor (Ahr), a ubiquitously-expressed transcription factor is activated by cigarette smoke and translocates into the nucleus upon activation. Ahr in GECs were activated and nuclear translocation was induced when treated with 1 or 10 µg/mL of CSC. Moreover, Ahr activation by 1 µg/mL of 2,3,7,8-tetrachlo rodibenzo-p-dioxin (TCDD) or CSC for 24 hrs upregulated the expression of ACE2.


However, TMPRSS2 expression levels did not significantly increase when treated with 10 µg/mL TCDD or CSC. This proves that Ahr activation is involved in the increase of ACE2, but not TMPRSS2. To analyze the effect of CSC on the internalization of the SARS-CoV-2 virus, GECs with or without TCDD (10 nM) or CSC (1 or 10 µg/mL) was infected with SARS-CoV-2 GFP-tagged pseudovirus and analyzed using immunofluorescence microscopy. It was observed that GECs treated with CSC at 10 µg/mL showed a significant increase in SARS-CoV-2 pseudovirus infection when compared to untreated cells. Similarly, CSC exposed GECs when treated with siRNA against Ahr showed lower levels of SARS-CoV-2 pseudovirus internalization.


Thus, Ahr-signalling dependent upregulation of ACE2 receptors due to CSC favors SARS-CoV-2 internalization and makes the smokers more susceptible to COVID-19 disease. Thus, Ahr-signalling dependent upregulation of ACE2 receptors due to CSC favors SARS-CoV-2 internalization and makes the smokers more susceptible to COVID-19 disease.


Source: International Journal Of Molecular Sciences

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