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Say No to Smoking, Say Yes to Cigarette Smoke-Mimicking Drugs: Novel Therapy May Reduce COVID-19’s Ability to Infiltrate Cells

Why are COVID-19 cases lower amongst smokers compared to non-smokers despite many reports suggesting that smoking increases the severity of the disease? Researchers uncover several possible reasons.

In the midst of developing efficacious vaccines and drugs to combat SARS-CoV-2, scientists have identified an anomalous relationship between COVID-19 and smoking cigarettes. While active smoking is often associated with the development and increased severity of disease, many reports have suggested that there are lower numbers of COVID-19 cases amongst smokers as compared to non-smokers.

“Something strange was going on here,” explained Keiji Tanimoto of Hiroshima University’s Research Institute for Radiation Biology and Medicine. “But we had a few ideas about how to tease out what some of the mechanisms at work might be.”

To clarify the relationship between smoking and COVID-19 infections, Tanimoto and his colleagues from Hiroshima University investigated how cigarette smoke extracts affect the pathogenesis of SARS-CoV-2. Their study led them to discover two drugs that can mimic the effect of chemicals in cigarette smoke to bind to a receptor in mammalian cells and potentially reduce the ability of the SARS-CoV-2 virus to enter cells.

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

It is known that cigarette smoke contains polycyclic aromatic hydrocarbons (PAHs), which binds to and activates aryl hydrocarbon receptors (AHRs). In mammalian cells, AHRs act as a transcription factor that can induce various cellular physiological and pathological responses by increasing or decreasing the expression of certain genes. Given this relationship between PAHs and AHRs, the researchers sought to determine how AHR-activating drugs affect the expression of genes that control the production of ACE2 protein, which is needed by the SARS-CoV-2 virus to infiltrate cells.

The team first studied various cell lines to examine their gene expression levels of ACE2. Their findings showed that cells originating from the oral cavity, lungs, and liver had the highest ACE2 expression. These high-ACE2-producing cells were then subjected to various doses of cigarette smoke extract for 24 hours, after which the scientists evaluated the rate of expression of another gene called CYP1A1, which is known to be inducible by the cigarette-smoke extract.

Their experiments revealed that treating the cells with cigarette-smoke extract increased the expression of CYP1A1 gene in liver and lung cells in a dose-dependent manner whereby the greater the dose, the greater the effect. Although this effect was not as pronounced in oral cavity cells, the team concluded that higher CYP1A1 activity caused a fall in the production of ACE2 receptors. To explain why this negative relationship was observed in the presence of cigarette smoke, the team further examined the cells using RNA sequencing analysis. By studying the gene expression of cells, they discovered that cigarette smoke extract increased the expression of genes that are related to some signalling processes regulated by AHRs.

To determine exactly how AHRs influence the expression of ACE2, Tanimoto and his colleagues tested two AHR-activating drugs, 6-formylindolo(3,2-b)carbazole (FICZ), a derivative of the amino acid tryptophan, and omeprazole (OMP), a medication already widely used in the treatment of acid reflux and peptic ulcers, on liver cells. According to RNA sequencing analyses performed on these cells, the AHR activators were able to strongly induce the CYP1A1 gene and inhibit the expression of ACE2, once again in a dose-dependent manner.

Encouraged by these findings, the team is now proceeding with pre-clinical and clinical trials on the drugs in hopes of developing a novel anti-COVID-19 therapy. [APBN]

Source: Tanimoto et al. (2021). Inhibiting SARS-CoV-2 infection in vitro by suppressing its receptor, angiotensin-converting enzyme 2, via aryl-hydrocarbon receptor signal. Scientific Reports, 11, 16629.