Fig. 2.

Hypothetical mechanism of nicotine-induced facilitation of SARS-CoV-2 entry into neurons through ACE2 receptors: SARS-CoV-2 can enter the central nervous system through different mechanism(s) (hematogenous spread, retrograde olfactory neuronal transmission, cytokine storm, and compromised blood-brain barrier) and bind to its proposed receptor, ACE2, almost exclusively in neurons. The virus then enters the neurons through endocytosis and starts replication, which could lead to a number of neurologic complications. In the brain, nicotine acts by binding to neuronal nAChRs and also interacts with the brain RAS. Nicotine exposure results in an upregulation of nAChRs, which can subsequently increase cell surface ACE2 expression. Excessive ACE2 could competitively bind with SARS-CoV-2 and enhance the viral entry and replication in neurons. This enhanced viral binding to ACE2 could in turn downregulate the expression of ACE2 receptor causing an imbalance in the brain RAS. As a result, the detrimental effects of Ang-II, mediated by AT₁R, would be increased, whereas the protective effects of Ang-(1–7) and Ang-(1–9), mediated by Mas receptor (MasR), would be decreased. The overall effects of these mechanisms could result in an excessive neuronal infection and damage by SARS-CoV-2.