Drugs that mimic the effects of cigarette smoke reduce the ability of SARS-CoV-2 to enter cells

Researchers have identified a potential reason why a lower number of COVID cases have appeared in smokers compared to non-smokers, although other reports suggest that smoking increases the severity of the disease.

Researchers have identified two drugs that mimic the effect of chemicals in cigarette smoke to bind to a receptor in mammalian cells that inhibits the production of ACE2 proteins, a process that appears to reduce the ability of the SARS-virus. CoV-2 to enter the cell.

Results appear in the journal Scientific reports August 17.

There is a paradox when it comes to smoking and COVID-19. Active smoking is associated with increased disease severity, but at the same time, many reports have suggested a lower number of COVID cases in smokers than in non-smokers.

“Something strange was happening here,” said Keiji Tanimoto of the Hiroshima University Research Institute for Radiobiology and Medicine, the corresponding author of the article. “But we had some ideas on how to determine what some of the mechanisms might be at work.”

“We must point out that there is strong evidence showing that smoking increases the severity of COVID-19,” Tanimoto added. “But the mechanism we discovered here deserves further investigation as a potential tool to fight SARS-CoV-2 infections.”

Cigarette smoke is known to contain polycyclic aromatic hydrocarbons (PAHs). These can bind and activate aryl hydrocarbon (AHR) receptors. A receptor is any structure on the surface or inside of a cell that is shaped to receive and bind to a particular substance. AHRs are a type of receptor inside mammalian cells that is in turn a transcription factor, something that can induce a wide range of cellular activities through its ability to increase or decrease the expression of certain genes.

Knowing this about the relationship between PAHs and AHRs, the researchers set out to study the effect of drugs that activate AHR on the expression of genes that control the production of the ACE2 protein, the infamous ACE2 receptor protein. the surface of many types of cells that functions as a lock that the SARS-CoV-2 virus is able to pick up. After binding the virus to the ACE2 protein, it can then enter and infect the cell.

First, scientists studied various cell lines to examine their levels of ACE2 gene expression. They found that cells from the oral cavity, lungs and liver had the highest ACE2 expression.

These cells with high ACE2 expression were then subjected to various doses of cigarette smoke extract (CSE) for 24 hours. After that, the level of expression of the CYP1A1 gene, which is known to be inducible by CSE, was assessed. CSE treatment induced increased expression of the CYP1A1 gene in liver and lung cells in a dose-dependent manner: the higher the dose, the greater the effect. However, this effect was not as pronounced in the cells of the oral cavity. In other words, more activity of CYP1A1, less production of ACE2 receptors, the route by which the virus is able to enter cells.

In order to explain why this happened in the presence of cigarette smoke, the researchers then used RNA sequencing analysis to more fully investigate what was happening with gene expression. They found that CSE increased expressions of genes linked to a number of key signaling processes within the cell that are regulated by PA.

To more directly observe this mechanism by which AHR acts on the expression of ACE2, the effects of two drugs that can activate AHR were evaluated on hepatic cells. The first, 6-formylindolo (3,2-b) carbazole (FICZ) is a derivative of the amino acid tryptophan, and the second, omeprazole (OMP), is a drug already widely used in the treatment of reflux. acid and peptic ulcers.

RNA sequencing data suggested that the CYP1A1 gene was strongly induced in liver cells by these AHR activators, and that ACE2 gene expression was strongly inhibited, again in a dose-dependent manner.

In other words, cigarette smoke extract and these two drugs, which all act as activators of AHR, are able to suppress the expression of ACE2 in mammalian cells and in doing so, reduce the capacity of the SARS-CoV-2 virus. to enter the cell.

Based on the lab’s results, the team is currently conducting preclinical and clinical trials on the drugs as a new anti-COVID-19 treatment.