Smoking May Exacerbate SARS-CoV-2 Infection by Increasing ACE2 Expression

This article, summarizing a paper just published in Developmental Cell, describes an interesting finding that fits with GEITP’s theme of gene-environment interactions: the environmental signal is “smoking” and the genome response includes “up-regulation of the ACE2 (angiotensin-converting enzyme-2) gene.” These data would suggest that ACE2 is part of the AHR-CYP1 axis that governs the expression of dozens if not hundreds of genes that are turned on in response to specific environmental and endogenous signals. In fact, induced ACE2 expression likely is secondary to stimulation of the pro-inflammatory processes, mediated by lipid mediator [e.g. downstream of arachidonic acid (AA), eicosopentaenoic acid (EPA), and docosahexaenoic acid (DHA) signaling] second-messenger pathways. [Reviewed in Progr Lipid Res 2017; 67: 38-57]


Smoking May Exacerbate SARS-CoV-2 Infection by Increasing ACE2 Expression

May 20, 2020

Whether smokers have a harder time dealing with a COVID-19 infection remains, like many questions surrounding this disease, a question without a firm answer. Previous data have suggested that cigarette smokers are more likely than non-smokers to have health complications. Now, a group of researchers present findings that may explain why.

Scientists from Cold Spring Harbor Laboratory (CSHL) found that smoking increases the gene expression of ACE2—the protein that binds SARS-CoV-2. The study suggests that prolonged smoking could cause an increase of the ACE2 protein in the lungs, possibly resulting in a higher rate of morbidity in patients.

“Our results provide a clue as to why smokers who develop COVID-19 tend to have poor clinical outcomes,” said senior author Jason Sheltzer, PhD, an independent fellow at CSHL. “We found that smoking caused a significant increase in the expression of ACE2, the protein that SARS-CoV-2 uses to enter human cells.”

The work appears in a paper in Developmental Cell titled, “Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract.”

ACE2, or angiotensin-converting enzyme-2, is a regulatory protein that has been linked to vulnerability to the 2003 SARS (2003) virus. “Evidence from mouse experiments has shown that higher levels of ACE2 make mice more susceptible to SARS,” said Sheltzer. More recent work with SARS-CoV-2 found that when human ACE2 was highly expressed in mice infected with the SARS-CoV-2 virus, they died more quickly.”

In humans, the lungs act as one of the primary locations of ACE2 production. To assess the direct impact of smoking on ACE2 expression in the lungs, Sheltzer compared ACE2 gene expression from the lung epithelial tissue of people who smoked cigarettes regularly to those who had never smoked. “We found that smoking caused a significant increase in the expression of ACE2,” said Sheltzer, who noted that smokers produced 30–55% more ACE2 than their non-smoking counterparts. This change was also dose dependent, with heavy smokers having the greatest ACE2 values.

The effects of smoking on ACE2 may be tied to the goblet cells in the lungs—one of the few lung cell types that Sheltzer found to actively express the ACE2 gene. “Goblet cells produce mucous to protect the respiratory tract from inhaled irritants. Thus, the increased expression of ACE2 in smokers’ lungs could be a byproduct of smoking-induced secretory cell hyperplasia,” said Sheltzer. An uptick in ACE2 was also associated with the inflammatory pulmonary diseases, COPD and idiopathic pulmonary fibrosis.

Additionally, Sheltzer’s results indicate that other viral infections, such as influenza, as well as interferon signaling—the part of the body’s virus defense system—also increase ACE2 expression. “Because of this, it’s conceivable that SARS-CoV-2 could trigger the upregulation of its own receptor, thereby creating a positive feedback loop leading to more infections,” Sheltzer said.

While the impact of cigarette smoke and ACE2 expression is compelling, it is not permanent. By comparing the lungs of current smokers to those who quit smoking for at least 12 months, Sheltzer found “a significant decrease in ACE2 expression, demonstrating that the effects of smoking on ACE2 can be reversed.” Further, other studies on the effects of cigarette smoke have shown mixed results. “Cigarette smoke contains hundreds of different chemicals. It’s possible that certain ingredients (like nicotine) have a different effect than whole smoke does,” said Sheltzer.

And while Sheltzer finds strong support for the upregulation of ACE2 gene expression from smoking, the actual ACE2 protein may be regulated in ways not addressed in this study. “One could imagine that having more cells that express ACE2 could make it easier for SARS-CoV-2 to spread in someone’s lungs, but there is still a lot more we need to explore.”

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