Cigarette Smoke Stimulates SARS-CoV-2 Internalization by Activating AhR and Increasing ACE2 Expression in Human Gingival Epithelial Cells

Abstract

A large body of evidence shows the harmful effects of cigarette smoke to oral and systemic health. More recently, a link between smoking and susceptibility to coronavirus disease 2019 (COVID-19) was proposed. COVID-19 is due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which uses the receptor ACE2 and the protease TMPRSS2 for entry into host cells, thereby infecting cells of the respiratory tract and the oral cavity. Here, we examined the effects of cigarette smoke on the expression of SARS-CoV-2 receptors and infection in human gingival epithelial cells (GECs). We found that cigarette smoke condensates (CSC) upregulated ACE2 and TMPRSS2 expression in GECs, and that CSC activated aryl hydrocarbon receptor (AhR) signaling in the oral cells. ACE2 was known to mediate SARS-CoV-2 internalization, and we demonstrate that CSC treatment potentiated the internalization of SARS-CoV-2 pseudovirus in GECs in an AhR-dependent manner. AhR depletion using small interference RNA decreased SARS-CoV-2 pseudovirus internalization in CSC-treated GECs compared with control GECs. Our study reveals that cigarette smoke upregulates SARS-CoV-2 receptor expression and infection in oral cells. Understanding the mechanisms involved in SARS-CoV-2 infection in cells of the oral cavity may suggest therapeutic interventions for preventing viral infection and transmission.

The Oral Cavity Potentially Serving as a Reservoir for SARS-CoV-2 but Not Necessarily Facilitating the Spread of COVID-19 in Dental Practice

“…Sakaguchi et al 8 Huang et al 12 Xu et al 21 Zhong et al 24 Almeida-da-Silva et al 25 Okui et al 26 Ohnishi et al 27 Periodontal tissue ACE2, Furin, and TMPRSS are expressed in periodontal tissues. SARS-CoV-2 is detected in the periodontal tissues of COVID-19 patients.…”

Oral Pathology in COVID-19 and SARS-CoV-2 Infection—Molecular Aspects

“…It was found that cigarette smoke condensates upregulated ACE2 and TMPRSS2 expression in human gingival epithelial cells. Moreover, this study provided evidence that exposure to cigarette smoke condensates potentiated the internalization of a SARS-CoV-2 pseudovirus in the cells in an AhR-dependent manner (AhR is a nuclear receptor that is a known mediator of cigarette smoke responses) [35]. Thus, the experimental findings suggest that smoking cessation could reduce the susceptibility to coronavirus infection of the oral cavity structures.…”

E-Cigarette Vapour Increases ACE2 and TMPRSS2 Expression in a Flavour- and Nicotine-Dependent Manner

“…This adds to the body of growing evidence that smoking is linked to a higher chance of infection with SARS-CoV-2. One study exposed gingival epithelial cells to cigarette smoke and showed increased ACE2 and TMPRSS2, as well as increased internalisation of SARS-CoV-2 via AChR signalling, which was able to be blocked by AChR RNAi [ 72 ], showing a direct link between smoke exposure, increased ACE2 and TMPRSS2, and increased viral uptake.…”