Smoking linked to increased expression of SARS-CoV-2 receptor

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Angiotensin Converting Enzyme 2 (ACE2) is a regulatory protein that is primarily produced in the lungs. It is also the protein that allows SARS-CoV-2 to infect and enter human cells. A study published in Developmental Cell has demonstrated that cigarette smoke can increase the expression of ACE2. The team at the Cold Spring Harbor Laboratory (CSHL; NY, USA) discovered ACE2 to be most actively expressed by goblet cells, whose increased production as a result of smoking may therefore increase an individual’s susceptibility to SARS-CoV-2 infection.

During the COVID-19 pandemic, there have been drastic differences observed in the way individuals react to SARS-CoV-2 infection. The majority of infected individuals suffer from mild symptoms that may go unnoticed, whereas others experience severe reactions that could result in hospitalization.

This study used single-cell sequencing data to examine the ACE2 gene expression in lung epithelial tissue of individuals who smoked cigarettes regularly compared with those who had never smoked.

Senior author Jason Sheltzer (CSHL) commented: “we started gathering all the data we could find. When we put it all together and started analyzing it, we saw that both mice that had been exposed to smoke in a laboratory and humans who were current smokers had significant upregulation of ACE2.”

Individuals who smoked cigarettes produced 30–55% more ACE2 protein, compared with those who had never smoked. This result was dose-dependent, with heavy smokers having the greatest ACE2 protein levels.

Further, the researchers demonstrated that ACE2 expression is responsive to inflammatory signalling and that SARS-CoV-2 infection has the potential to create positive-feedback loops. Together, these factors increase ACE2 expression and facilitate viral dissemination. Therefore, the team concluded that cigarette smoking increases ACE2 expression, which may explain why cigarette smokers are more susceptible to severe SARS-CoV-2 infection.

“Our results provide a clue as to why smokers who develop COVID-19 tend to have poor clinical outcomes,” explained Sheltzer.” Evidence from mouse experiments has shown that higher levels of ACE2 make mice more susceptible to SARS. More recent work with SARS-CoV-2 found that when human ACE2 was highly expressed in mice infected with COVID-19, they died more quickly.”

However, the susceptibility to SARS-CoV-2 contraction can be reversed. Data collected from individuals who currently smoke cigarettes and individuals who stopped smoking for at least 12 months demonstrated that quitting smoking significantly decreased the abundance of goblet cells and ACE2 expression in the lungs. Therefore, quitting smoking may reduce the risk of severe SARS-CoV-2 infection.

Sheltzer commented: “cigarette smoke contains hundreds of different chemicals. It’s possible that certain ingredients (like nicotine) have a different effect than whole smoke does. Commenting on the limitations of the study, he also noted: “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.”

Sources: Smith JC, Sausville EL, Girish V et al., Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract. Dev. Cell. (2020). doi:10.1002/anie.202002979; www.cshl.edu/smoking-increases-sars-cov-2-receptors-in-the-lung/www.eurekalert.org/pub_releases/2020-05/cp-sml051820.php

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