New data suggests smokers have a much higher risk of COVID-19 complications than non-smokers, but the reasons why are not understood. One recent study suggests that the reason may be increased ACE2 gene expression in smokers, which would make it much easier for the SARS-CoV-2 virus to enter cells in the airways.
SARS-CoV-2 gains access to cells by binding to Angiotensin Converting Enzyme 2 (ACE2), which is present on the surface of many cells in the body, including cells in the airways. Researchers at Cold Spring Harbor Laboratory (CSHL) found smoking increases expression of the ACE2 gene, which means more ACE2 will be present, giving the virus a better chance of binding and gaining entry into cells. That could explain why there is greater rate of morbidity in patients who are smokers.
The 2003 coronavirus that causes SARS – SARS-CoV -similarly uses ACE2 to gain access to cells. Studies conducted on mice have shown that mice with higher levels of ACE2 are more susceptible to SARS. The researchers conducted tests on mice using SARS-CoV-2 and found that mice with high levels of ACE2 died more quickly from COVID-19.
The researchers assessed ACE2 gene expression in smokers and non-smokers and found that smoking caused a significant increase in ACE2 expression. Smokers had between 30% and 55% higher levels of ACE2 expression than non-smokers, with the greatest level of ACE2 expression found in heavy smokers.
The ACE2 gene is actively expressed in the goblet cells in the lungs, which are responsible for producing mucus. “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,” explained Jason Sheltzer, PhD, independent fellow at CSHL, and senior author of the study.
The study also strongly suggests ACE2 is upregulated by other viral infections in the lungs such as influenza, the ACE2 gene is upregulated by interferon exposure and inflammatory signalling is also linked to ACE2 expression, such as with COPD and idiopathic pulmonary fibrosis. Upregulation of ACE2 gene expression caused by smoking is not permanent. Sheltzer found that individuals who had quit smoking for more than 12 months saw a significant decrease in ACE2 expression.
The research also adds weight to the findings of other studies which suggest SARS-CoV-2 triggers the upregulation of its own receptor, creating a positive feedback loop that leads to more cells being infected.
You can read more about the study in the paper – Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract – which was recently published in Developmental Cell. DOI: 10.1016/j.devcel.2020.05.012